Infection with the human immunodeficiency virus type 1 (HIV-1) results in progressive loss of immune function marked by depletion of the CD4+ T-lymphocytes, leading to opportunistic infections and malignancies characteristic of AIDS. Although both host and viral determinants influence the rate of disease progression, the median time from initial infection to the development of AIDS among untreated patients ranges from 8 to 10 years. The clinical staging of HIV disease and the relative risk of developing opportunistic infections historically relied on the CD4+ T-lymphocyte counts. Although more recent studies have shown the importance of viral load quantitation in determining the rate of disease progression, it is still useful to categorize HIV disease stage on the basis of the degree of immunodeficiency: early disease (CD4+ > 500 cells/mL), mid-stage disease (CD4+ between 200 and 500 cells/mL), and end-stage disease (CD4+ < 50 cell/mL). This article reviews the natural history of HIV disease at each stage of HIV-1 infection with emphasis on acute infection and the major virologic and immunologic determinants of disease progression.