Significant progress has been made in the field of human immunodeficiency virus (HIV) pharmacotherapy. This is a remarkable achievement given that the virus was first recognized in the United States in 1981 and the first antiretroviral (ARV) agent became available in 1987. There are now 20 medications in 4 different classes approved by the Food and Drug Administration (FDA) for the treatment of HIV and the carefully orchestrated use of these agents has dramatically decreased HIV mortality. However, the currently available agents have concerning limitations. These include potentially life-threatening side effects, drug interactions, loss of effectiveness over time due to resistance and the need for an extremely high level of medication adherence to achieve viral suppression. In the following review, important features of the presently available agents are described, and the characteristics of an ideal ARV agent defined.