The remarkable effectiveness of combination antiretroviral therapy (CART) in the treatment of HIV infection has placed a high premium on long-term adherence to therapy. Adherence levels to CART among HIV-infected individuals are similar to adherence levels with chronic medical conditions, such as diabetes and hypertension. However, unlike chronic medical conditions, medication adherence that is insufficient to maintain suppression of HIV replication will lead to drug resistance. Combination antiretroviral therapy regimen complexity and side-effect burden are clearly linked to adherence and are likely to be the factors most amenable to intervention. Adherence interventions that are multifaceted, flexible, and protracted are the most likely to be successful. Owing to the great benefits of CART even the small to modest gains in adherence that are achievable with adherence programs may prove to be cost effective.