One of the remaining mysteries of HIV infection is what causes the destruction of the CD4+ T cells. Several reports in the past year have linked viral load to disease progression, strengthening the conclusion that the virus is responsible for CD4+ T-cell depletion. We discuss several possible mechanisms of T-cell death, including the killing of uninfected CD4+ T cells. We also discuss the possibility that the virus protects the cell it infects at least until viral replication can be completed.