The 16th Conference on Retroviruses and Opportunistic Infections featured a strong and balanced program that showcased exciting research into cellular restrictions that defend the cell against viral infection as well as cellular cofactors that regulate central steps in viral replication. Immunopathogenesis presentations continued to reveal some surprises such as evidence for pathogenicity in natural simian immunodeficiency virus infection. The identification of novel cellular restrictions and cellular cofactors of viral replication indicate the possibility of numerous opportunities for the development of novel therapeutic agents for the treatment of HIV and AIDS.