There is a widespread acknowledgment that successful treatment with highly active antiretroviral therapy (HAART) requires the patient to maintain consistent adherence to the prescribed regimen on a long-term basis. Adherent patients have been shown to have reduced viral loads and increased CD4 counts, live longer, and have better quality-adjusted survival. The consequences of nonadherence are also obvious: poorer adherence leads to inadequate viral suppression and continued disease progression. With the astonishing advances in medical therapeutics during the past two decades, one may expect a similar proliferation of studies of the nature of nonadherence and tests of strategies to help patients overcome it. However, the literature and the know-how concerning interventions to improve adherence are still surprisingly weak. The unique challenges posed by combination therapies for HIV and AIDS require healthcare providers to address the issues created by adherence to complex regimens through multifactorial interventions tailored to patients' needs.