Basic science research constitutes a steadily increasing part of the Conference on Retroviruses and Opportunistic Infections, and the 12th conference arguably had the strongest showing of basic science research. Presentations on cellular defense factors dominated the basic science category, and some of the presentations provided a few surprises with regard to the mechanism by which the cellular defense factor APOBEC counteracts HIV-1 infection. A second cellular defense factor has been identified in the past year and a number of presentations focused on its mode of action. Similarly, evidence for new cellular factors that positively promote viral replication were presented. Novel findings relating to viral pathogenesis were featured at the meeting and some clarity was brought to the issue of the underlying role of viral pathogenicity and immune activation in lymphocyte depletion. The crystal structure of an unliganded SIV envelope was presented and has broad significance in terms of understanding viral infection and generating better immunogens for vaccines.