In this article, we discuss how human immunodeficiency virus (HIV) infection of activated CD4+ cells, expressing the chemokine receptors CCR5 or CXCR4, results in severe immunosuppression while evading the immune response. We describe how infection through mucosal surfaces or via the parenteral route results in rapid spread of the virus throughout the body prior to a vigorous CD8+ cytolytic T cell response, resulting in establishment of a viral set point. Data is examined that suggests the half-life of HIV virions in circulation is less than 6 hours and possibly as short as 30 minutes, whereas that of infected CD4 T cells is on average 1 to 1.5 days. We also explain how the rate of viral replication dictates the rate at which HIV evades the immune response and the rapidity with which resistance to antiviral medications may develop. Lastly, we show how anatomic and cellular reservoirs of latent viral pools have made the long-term goal of complete virus eradication difficult despite enormous advances in our therapeutic armamentarium.