Sex chromosomes are important for proper sexual differentiation. Females carry two X chromosomes (46,XX), whereas males carry one X chromosome and one Y chromosome (46,XY). The SRY (sex-determining region of Y chromosome) gene is located on the Y chromosome, and directs the development of the foetal gonads into testes, although many other genes are also important for proper sexual development of the male foetus. When two (or more) X chromosomes are present in a cell (as in healthy females or in sex chromosome disorders like 47,XXY), only one is active. The additional X chromosome is mostly inactivated, and the condensed X chromatin can be seen as a Barr body in the periphery of the cell nucleus. The genes located in the two small pseudoautosomal regions (PAR) remain active in both men and women; therefore, men with KS are functionally trisomic for these genes. In addition, some genes in the region of the X chromosome, which are not homologous to the Y chromosome and thus are normally inactivated, do escape inactivation, and these genes are functionally duplicated in KS males (analogous to the situation in females). Following the first publication by Klinefelter et al. (1) on the clinical phenotype of KS in 1942, and the discovery by Jacobs and Strong in 1959 that the aetiology was an abnormal chromosome constitution with an extra X chromosome (2), several early research papers reported a heterogeneous symptomatology of men with the 47,XXY karyotype. However, during recent decades there has been relatively little further basic or clinical research in this area. In comparison, many more papers have been published regarding girls with the much rarer condition Turner syndrome, particularly because the use of growth hormone was introduced for the management of the disorder. Therefore, our basic knowledge of the genetic, endocrine, psychological and social aspects of KS, remains very limited. Even relatively simple and practical questions concerning its management have not been fully addressed. Since our department was established in 1990, we have cared for more than 200 patients with KS, and have carried out a number of research projects (3). However, we still have more questions than answers; in fact, the number of questions concerning KS is sharply increasing. Therefore we felt that the time was ripe to gather a group of leading researchers in paediatrics, endocrinology, genetics and psychology for a workshop on KS. Thus, a workshop was held on 6–8 May 2010 at Rigshospitalet, Copenhagen University Hospital. The participants considered several questions, only some of which could be answered. However, as seen on the following pages in this special issue of Acta Paediatrica containing the proceedings, many research ideas were presented during the meeting. What every paediatrician should know about Klinefelter syndrome (KS): KS results from an additional X chromosome (47,XXY) and is the most common sex chromosome disorder (1–2 per 1000). By contrast, the lack of an X chromosome in females results in Turner syndrome (45,X), which is much less common Only 25% of patients with KS are ever diagnosed (i.e. KS often remains unrecognised) Boys and adolescents with KS tend to grow more than average and may show eunuchoid body proportions, and 50% develop gynaecomastia in puberty which may persist into adult life Many boys with KS have delayed speech and learning difficulties in school Boys with KS may show psychosocial problems, and impaired interaction with peers In KS, puberty is initiated at a normal pace, but because of testicular insufficiency individuals fail to obtain normal luteinizing hormone and testosterone levels in young adulthood. All males with KS have small testes (maximum volume of 6 mL by orchidometry) during puberty and in adult life The following is a list of some of our pre-workshop questions. Which of the genes that escape X- inactivation in KS are to blame for the clinical symptoms? Is the same combination of genes responsible for all KS symptoms, or are different genes/combinations of genes responsible for different symptoms, e.g. increased growth, seminiferous tubule hyalinization or neurodevelopmental symptoms? Does it matter whether the extra X is of paternal or maternal origin? Are there geographical and racial differences in the frequency of KS? Is the incidence of KS increasing? Why is there always a sudden destruction of seminiferous tubules in mid-puberty, but not much atrophy before then? Why are there often patches of preserved seminiferous tubules, even in testicular biopsies from adults with KS who present with azoospermia? Why are there often both differentiated and undifferentiated Sertoli cell only tubules in the same biopsy in patients with KS? Why is there no Barr body in the differentiated Sertoli cells in KS, although the karyotype is non-mosaic 47,XXY? Is the reported significantly increased risk of breast cancer in KS due to gynaecomastia alone, or are there direct effects of overexpressed genes on the X chromosome? How is adrenal function affected by KS? What is the role of hypogonadism with regard to the reported increased risk of metabolic syndrome in KS? When should testosterone treatment be initiated (postnatally, during puberty or in adulthood)? Does early testosterone treatment in puberty diminish the chances of later fertility? How should we manage fertility problems? Besides the reproductive system, are there other targets for androgen administration in KS? Are there patients in whom we should be cautious with androgen administration? Can early testosterone treatment prevent gynaecomastia and osteoporosis? What is the biological mechanism of the wide range of neuropsychological symptoms in KS? Is early diagnosis of KS of benefit? Should we screen for KS? Why is there a risk of mediastinal germ cell cancer in KS? How should we manage the cardiovascular system in KS? How should we manage the psychosocial problems in KS (during childhood, puberty and adulthood)? Not all these questions could be answered and more questions were added during the course of the meeting. However, in many cases, new research strategies to tackle unanswered questions arose from lively discussions during the meeting. In conclusion, KS, a syndrome that affects 1–2 per 1000 males, is not only challenging for patients and their families, but also for professionals who need a much better scientific foundation for decision-making as part of patient care. Despite the fact that we now have much better research tools than 60 years ago when the syndrome was first described, relatively little research has been carried out in comparison to other clinical conditions. One obstacle has been that management, which must be a life-long process in KS, is often split between paediatricians, who take care of boys with KS, and andrologists and endocrinologists who manage fertility problems and androgen insufficiency later in life. However, we should consider a life-long perspective from birth to old age when determining KS management strategies to include available knowledge and experience on all aspects of KS throughout life. Therefore, more interdisciplinary collaboration between paediatricians, endocrinologists, geneticists, molecular biologists, psychologists and sociologists should be established. As seen from the proceedings presented in this issue, all these specialities were represented at the workshop. Thus, a wealth of new information is presented in the articles as well as in the edited discussions between leading scientists working in both clinical and basic areas of KS.