Medication adherence to highly active antiretroviral therapy (HAART) is currently a topic of major importance in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome care. HAART has dramatically reduced morbidity and mortality from HIV infection. Many people with HIV now live active and productive lives, with the disease itself having minimal impact on their lifespan. Unlike treatment for other chronic diseases, achieving the full benefit of HAART requires an extremely high level of adherence to potent antiretroviral combinations that is often difficult to achieve given the high pill burdens, drug interactions and adverse events associated with treatment. In this paper, the present knowledge regarding antiretroviral medication adherence is summarized with a focus on understanding the importance of adherence, the relationship between adherence and treatment response, the challenges and barriers facing patients trying to achieve optimal adherence, reasons for nonadherence, and the current directions and issues relevant to future adherence research.