High levels of adherence to antiretrovirals are important to prevent the development of genotypic resistance and achieve virologic suppression. Although the decreased complexity of regimens is associated with improved adherence, there is little evidence that adherence is better with once-daily dosing regimens compared to twice-daily regimens. The relationship between adherence, resistance, and virologic suppression is different for different classes of antiretrovirals. Boosted protease inhibitor (PI)-based regimens are preferred to unboosted PI-based regimens for patients with poor adherence. With PI-based regimens, the pharmacologic consequence of a single missed dose is greater with a once-daily regimen than with a twice-daily regimen (e.g., once-daily versus twice-daily lopinavir/ritonavir). Although resistance is a concern for patients taking non-nucleoside reverse transcriptase inhibitor-based regimens with imperfect adherence, virologic suppression can be achieved with less than 95% adherence. It is important for clinicians to address adherence problems in their patients and to tailor individual regimens based on treatment history, genotype resistance, side effect profile, drug interactions, pharmacokinetics, schedule preferences, and perceived adherence.