Oncogenic, high-risk human papillomaviruses (HPV) have, in less than four decades, become the showcase of translational science. Harald zur Hausen first suggested the concept of oncogenic high-risk HPV in 1975, before confirming HPV’s link to cervical cancer in 1983; work which led to him being awarded the 2008 Nobel Prize for physiology and medicine [1,2]. Then, between 1996 and 2001 HPV were proven to cause increased risk for later development of carcinomas of the uterine cervix, other anogenital sites and the oropharynx [3–5], before being shown to be preventable between 2002 and 2012. In clinical trials, efficacy of the two licensed vaccines against genital infections with the two most important high-risk HPV types, 16/18, and their neoplastic sequelae – most notably cervical intraepithelial neoplasia grades 2/3 (CIN2/3) – have been between 97 and 100% with tight, albeit overlapping 95% CIs (for a recent review of this topic, see the 2012 work by Lehtinen et al. [6]). Overall, vaccine efficacy (VE) against CIN3 also appears to be almost too good to be true (>93%), but numbers of incident clinical trials or cancer-registry follow up-based end point cases are still limited. So far, observations of VE against the most stringent cervical adenocarcinoma in situ, as well as CIN3 end points, are based on small numbers [6,7]. These, and other still missing HPV-associated cancer end points, need to be verified in the future. It is especially important to verify and exploit wide-spread cross-protectivity of the currently licensed vaccine(s) against a number of oncogenic HPV types and their sequelae [8]. A substantial lag period existed in gathering convincing evidence on the impact of hepatitis B virus vaccination programs, implemented in 1984 in Taiwan and Alaska on hepatocellular carcinoma, since it was 25 years before a 90–100% reduction in the hepatocellular carcin incidence was achieved [9,10]. In the case of HPV, an even longer lag period in completing this kind of a chain of evidence via national HPV vaccination programs was imminent. This is because the age-peaks of high-risk HPV infections and cervical cancer are between 18 and 22 and at approximately 45 years of age, respectively [11]. Thus, from vaccination of early adolescents it would take 30 years to start to see the impact of HPV vaccination on cervical cancer incidence, and long-term follow up of sizeable population-based clinical trial cohorts, enrolled approximately 10 years ago in Costa Rica, Finland and the Scandinavian countries, is pivotal [12,13]. The major flaw in the originally US FDA-approved CIN2 surrogate end point is that it has proven to be irreproducible and unstable [14,15], which makes inferences on the probable HPV VE against overall invasive cervical cancer (ICC) vague. It is, however, not only about getting convincing evidence on the VE against ICC, but evidence on the VE against other HPV-associated cancers as well.