Adherence to treatment regimens is essential to the success of highly active antiretroviral therapy (HAART) in patients infected with HIV. Multiple research studies have clearly demonstrated the close association between proper adherence to HAART and decreases in both plasma HIV RNA levels and HIV-associated mortality rates. In an effort to maintain virologic suppression, adherence levels of 95% are required for patients treated with HAART. However, community reports suggest that actual adherence levels are often far lower than those required for successful HAART; many studies show that 40% to 60% of patients are less than 90% adherent. Multiple reasons for nonadherence to HAART regimens have been reported by patients infected with HIV. Patients with mental illness (e.g., depression) are more than seven times more likely not to adhere to HAART regimens compared with patients without mental illness. Substance abuse is also a major barrier to adherence, with approximately 66% of HIV-infected intravenous drug users reporting suboptimal adherence to HAART regimens. Other barriers to adherence include uncertainty about both the effectiveness of treatment and the consequences of poor adherence, regimen complexity, side effects of treatment, and lack of social support. This article will discuss the strategies that should be used by all members of the multidisciplinary team treating patients with HIV/AIDS to encourage patient adherence to treatment. These strategies include educating and motivating patients, simplifying treatment regimens and tailoring them to individual lifestyles, preparing for and managing side effects, and addressing the concrete issues that may present barriers to adherence. In addition, adherence-boosting interventions that have established efficacy in controlled trials, such as motivational interviewing, and nurse-based interventions for patient populations with low health-literacy will be reviewed.