New insights into HIV pathogenesis have come from detailed analyses of viral clearance and evolution in small numbers of infected people. Rapid viral replication has been linked with rapid T cell turnover in patients in the latter stages of HIV infection. Rapid replication leads to frequent viral mutations that allow escape from antiviral therapy and perhaps host immune responses as well. Ultimately, failure of the homeostatic mechanisms that maintain total T cell number precedes clinical immunodeficiency. Studies of aggressive antiviral treatment early in the course of infection are needed to determine if disease progression and the emergence of drug resistance can be prevented.