Haemophilia has been known for thousands of years and Jewish writings from the 2nd century ad describe a ruling from Rabbi Judah the Patriach, which exempted the third son of a woman from being circumcised if his two elder brothers had died of bleeding after circumcision 1. The modern era of haemophilia started much later and it was not until the late 1940s and early 1950s that the two forms of haemophilia were recognized 2. Before the advent of factor concentrates, the expected median survival in a person with severe haemophilia was close to around 30 years. During the 1950s, concentrate development began when Birger and Margareta Blombäck in Sweden found that Cohn fraction I-O was enriched in factor (F) VIII 3, 4 and also in von Willebrand factor. The product was manufactured on an industrial scale by Kabi in Stockholm and studied in patients by the Blombäcks together with Inga Marie Nilsson 5. Figure 1 shows these pioneers at a meeting in Rome in the mid-1950s when they presented their important findings. The ground was laid for starting effective treatment of patients with haemophilia and also prophylaxis was started on a small scale. A few years later, cryoprecipitate was developed by Judith Pool 6 and became the dominating concentrate for many years. Factor IX concentrates were developed later 7. During the 1980s, development of haemophilia treatment protocols was severely jeopardized by the problems with transmission of blood-borne agents. When safe products became generally available during the late 1980s and especially with the advent of recombinant products in the early 1990s, a new era could focus on effective replacement therapy. Demographic studies of haemophilia by Ramgren 8 and Ahlberg 9 showed that persons with haemophilia with FVIII or IX levels above 1% of normal rarely develop severe arthropathy. The possibility to convert severe haemophilia to a mild form by prophylaxis was hypothesized. These clinicians worked closely together with Inga Marie Nilsson, who during the 1950s, and together with the group in Stockholm, had started to give regular infusions of anti haemophilia globulin to patients with severe haemophilia. The beneficial role of prophylaxis was indicated, although the regimen used was much less intensive compared to modern haemophilia prophylaxis. Early reports of prophylaxis also came from The Netherlands where Simon van Creveld in Utrecht was a pioneer in haemophilia treatment 10, 11. However, it should also be recognized that several other authors in Europe and North America reported results with prophylaxis during the 1960s and 1970s 12-18. These reports were on small cohorts and short follow-up time but the design was often scientifically sound. The first large report of long-term outcome of patients receiving prophylaxis came in 1992 from Nilsson et al. 19. This is the cohort published covering all age groups with the longest follow-up time. Sixty-six patients had been followed for up to 25 years and all had severe haemophilia, including nine with haemophilia B. Outcomes measured were bleeding frequency and joint disease. The latter was assessed using the physical examination score endorsed by the World Federation of Hemophilia (WFH) and developed by Marvin Gilbert and called the Gilbert score 20, and the more sensitive radiological score developed by Holger Pettersson was usually called the Pettersson score 21. The findings were compared with a historical group of patients who had been treated on demand. The results showed that prophylaxis, if started early and keeping trough levels essentially above 1%, could practically abolish the development of joint disease. Patients who started prophylaxis long ago had a less intense regimen and started at an older age. They developed some joint disease but had still much better outcome than younger patients treated on demand. In a large international study performed during the early 1990s and published in 1994 22, Aledort et al. confirmed the Swedish results. In this 6 year study on patients below the age of 25 with severe haemophilia without inhibitors, orthopaedic outcomes were superior in patients on prophylaxis who also reported less absent days from school and work. Interestingly, they also reported that 10% of patients with severe haemophilia had so-called ‘zero’ joints also when treated on demand. Obviously, a mild bleeding phenotype existed where joint disease did not develop as assessed using the above mentioned physical and radiological scoring systems. These studies were followed by several reports where prophylaxis clearly showed superior results compared to on-demand treatment. In the Norwegian-Swedish comparative study, it was demonstrated that on-demand-treated patients had five times more episodes of surgery and more resource use outside the healthcare sector but, of course with a much higher use of concentrate in the prophylaxis group 23, 24. In a comparison of the Dutch, primarily prophylactic regimen, and the French, on demand treatment 25, it was shown that prophylaxis was superior in young adults at the same cost. In Europe, it was evident in several countries as early as the 1970s, or even earlier, that prophylaxis was the state-of-the-art treatment, at least in children. However, as pointed out in the recent Swedish Health Technology Assessment of Hemophilia 26, the scientific evidence of these studies was low even if the effects were high. In countries where prophylaxis had a long tradition, it was considered unethical to perform randomized studies, but in countries where treatment on demand still was best practice, well-designed studies were started where patients were randomized between prophylaxis and treatment on demand. The first such study, from the United States, was published in 2007 27 and the second one, from Italy, in 2011 28. The results could now, with high scientific evidence, confirm the European cohort studies and prophylaxis finally became accepted in North America. In the meantime, other groups tried to evaluate different prophylactic regimens in order to increase cost efficacy and convenience. Comparative studies between the Dutch and Swedish regimens have been reported 29 and in Canada a dose escalation protocol has been used 30. More long-term data are needed until firm conclusions can be drawn. An important milestone in prophylaxis is when there was more focus on true primary prophylaxis. It was evident from several studies that starting prophylaxis early had a paramount effect on long-term outcome. This had been shown in Sweden 31 in 1991 when, in a small number of children, those who started by the age of 3 years had a better outcome than those starting at the age of 5 years. In a nationwide study, this could be clearly confirmed 32 in 1999. Later on, primary prophylaxis was better defined by international groups. A problem is that it seems difficult to delineate when cartilage destruction starts. This was highlighted in the US prophylaxis study by Manco-Johnson et al. 27: using MRI, joint disease was shown in some children who had not even experienced clinical bleeding. The concept of subclinical bleeds became important for prophylaxis dose regimens. It is no longer controversial that prophylaxis is the state-of-the-art treatment but there are still many open issues such as: when to start; when or rather if to stop; how to dose; and how to assess. The traditional assessment tools, i.e. radiography according to Pettersson 21 and physical examination according to the WFH 20, are more and more being replaced by MRI and ultrasonography 33, 34. Health economy and quality of life assessment have become important. To address many of these issues, the International Prophylaxis Study Group was formed in 2001 35. Pharmacokinetics have become a requisite for prophylactic dosing. During the 1990s, it could be shown that shortening of dose interval, keeping trough levels, reduced cost at sustained prophylactic efficacy 36, 37. Even daily dosing has a potential to be feasible in some patients 38. Pharmacokinetics have more recently been studied in larger international cohorts 39, 40 and the trend is to personalize dosing according to clinical response and individual pharmacokinetics. Long-acting FVIII and FIX concentrates are under study and have a potential to improve prophylaxis, either by using longer intervals than with traditional products, or by raising trough levels. Longer intervals for dosing would improve convenience and compliance. Raising the trough levels has a potential to dramatically increase the long-term medical effect as even patients receiving so-called high-dose prophylaxis have substantially reduced levels compared to haemostatically normal people. Cost remains the main hurdle for prophylaxis and therefore perhaps the most important wish for the future, irrespective of the type of concentrate used, is a price reduction Gene therapy and cure of haemophilia will totally change the history, but that is another story. The author stated that he had no interests which might be perceived as posing a conflict or bias.