Fourteen years into the global epidemic of the acquired immunodeficiency syndrome, the exact mechanisms by which the human immunodeficiency virus (HIV) causes the destruction of the immune system remain unresolved. Infection with HIV is characterized by both continual virus replication and a vigorous immune response. The length of time from initial infection to the almost inevitable loss of CD4 positive T helper lymphocytes averages 10 years, indicating the dramatic and prolonged interplay of the virus and the host immune response. In this article we discuss many of the leading hypotheses for both direct and indirect mechanisms that have been proposed to explain the loss of CD4 cells. Current evidence suggests strongly that direct infection of CD4 cells is adequate to explain their loss, but that cofactors and indirect mechanisms may contribute to the overall process. This leads to the conclusion that the immunopathology of HIV infection can be most effectively countered by using antiretroviral chemotherapy.