The management of HIV disease has evolved into a complicated and sophisticated subspecialty in recent years. Fourteen drugs, in various combinations, are being used in increasingly complex treatment regimens. The side effects of some of these drugs, as well as certain drug-drug interactions may mimic signs and symptoms of HIV disease itself. Therefore it is imperative for the emergency physician to be knowledgeable about the new medications as well as about selected adverse effect and drug interaction profiles in order to be able to take care of the increasing numbers of HIV-positive patients presenting to emergency departments. This article aims to provide a focused review of these topics. In addition, health care workers with significant exposures to HIV-infected body fluids may present to the emergency department for initial evaluation. This presents a situation whereby emergency physicians may have to prescribe appropriate combinations of antiretroviral agents themselves. Thus familiarity with the basic principles of post-exposure prophylaxis is desirable and current Centers for Disease Control and Prevention guidelines are briefly reviewed.