Complicated dosing regimens can unfavorably affect patient adherence and drug efficacy. In an effort to increase adherence while maximizing the benefits of the protease inhibitor (PI) component of HAART, the efficacy and safety of less frequent PI dosing regimens have recently been under scrutiny. Limiting the number of drugs required in antiretroviral therapy regimens may also minimize toxicity and drug-drug interactions. This article reviews the current movement toward twice-daily regimens and examines the efficacy and safety data available on twice-daily dosing of amprenavir, indinavir, nelfinavir, saquinavir soft-gel capsules, and ritonavir. Future trends in dosing are also discussed.