Despite multiple studies demonstrating the relation between the success of highly active antiretroviral therapy (HAART) and adherence, inadequate adherence continues to be one of the most frequent reasons for poor treatment outcomes and/or lack of sustained treatment benefits. Interventions targeting patient-related social and psychologic barriers to adherence and issues related to mental health and substance abuse and access to health care may ameliorate their negative impact on adherence. Specific drug-related factors that influence adherence such as pill burden, dosing frequency, food requirements, and acute tolerability and safety concerns, however, are further issues that must be considered to optimize adherence. Fortunately, the availability of once-daily and coformulated agents with simple dosing requirements may help to improve adherence, and thereby make the difference between success and failure of HAART for some patients. A better understanding of adherence and its determinants and how to define specific goals in a given clinical setting are keys for clinicians to become more effective partners with patients in the achievement and maintenance of long-term virologic suppression and, more importantly, long-term health.