A constant and nearly absolute adherence is required to ensure a successful long-lasting outcome of highly active antiretroviral therapy (HAART). Pill burden and regimen complexity are important contributors to adherence problems. The most significant treatment-related strategy to improve adherence may be the reduction in the number and frequency of pills to be taken every day. If one accepts the concept that once-daily therapy is likely to benefit patients, then the issue turns to whether we have adequate drugs to implement once-daily HAART. There is quite a difference between using a once-a-day drug within an HAART regimen and designing an HAART regimen that is dosed once daily. To date, studies that explore the feasibility of once-a-day HAART regimens are still few, mostly exploratory, not controlled, and performed in a limited number of patients. However, most data are consistent one with the other, and evidence on the utility of such regimens is growing. Once-daily therapy cannot be the answer to all the questions that complex and life-long therapies give rise to, but it could be a further choice that can meet the needs of many patients. The range of once-daily options is expanding rapidly, and the patients' request for easier therapies that are respectful of their lifestyle could be fulfilled.