Highly active antiretroviral therapy (HAART) has been a major breakthrough for the treatment of patients with HIV; however, adherence to treatment remains a formidable barrier. This paper evaluates the current state-of-the-science in adherence to HAART. Barriers to treatment success, determinants of adherence and interventions to improve adherence are reviewed. Overall, multifaceted interventions appear most promising. We conclude with recommendations to enhance clinical practice and improve treatment outcomes for patients with HIV. Despite substantial attention to adherence in recent years, much more remains to be done to understand and promote adherence to HAART.