Adherence to therapy is of critical importance for the long-term success of the treatment of HIV infection. Once-daily administration of antiretroviral agents is appealing, as it may increase patient's adherence. The pharmaceutical industry is making huge efforts to develop drugs or combinations of drugs with pharmacokinetic properties allowing once-daily administration. The major pharmacokinetic requirement for once-daily administration is that the intracellular concentration of the antiretroviral or its active metabolite remains above the minimal concentration that can inhibit viral replication during the entire 24-hour period. Soon, all three major classes of antiretroviral agents will be available as once-daily formulations. However, only a few clinical trials have yet assessed the efficacy and safety of truly once-daily antiretroviral combinations. Preliminary results from these small pilot studies suggest that once-daily administration of antiretrovirals is a feasible approach. Large comparative trials are needed before the real benefits of such a strategy can be fully assessed.