Much of our knowledge about HIV infection has been obtained from cohort studies, including description of the natural history of infection, identification of CD4 count and viral load as good surrogate markers of clinical progression, identification of co-factors [including older age and viral infections (CMV, HCV)] for progression of HIV-related disease and assessment of impact of highly active antiretroviral therapy on clinical outcomes. The Cologne-Bonn cohort was founded by Gerd Fätkenheuer and Bernd Salzberger after introduction of combination antiretroviral therapy in 1996 and has delivered important findings which have helped to improve treatment strategies as well as quality of overall care in HIV infection in these two cities. Indeed, the first pivotal paper from the cohort reported on an unexpectedly high rate of virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. The subsequent analysis of risk factors for virological failure initiated the development of more potent HIV combination therapy. This review summarizes some of the major findings and contributions from the Cologne-Bonn cohort since 1996.