Early views on the relationship between adherence and resistance postulated a bell-shaped relationship that balanced selective drug pressure and improved viral suppression along a continuum of adherence. Although this conceptual relationship remains valid, recent data suggest that each regimen class may have different adherence-resistance relationships. These regimen-specific relationships are a function of the capacities of resistant virus to replicate at different levels of drug exposure, which are largely, but not entirely, determined by the impact of mutations on susceptibility of the virus and the impact of the mutations on the inherent ability of the virus to replicate efficiently. Specific patterns of adherence, such as treatment discontinuations, may influence adherence-resistance relationship to combination regimens comprised of medications with differing half-lives. Host genomics that alters antiretroviral drug distribution and metabolism may also impact adherence-resistance relationships. Optimal antiretroviral regimens should be constructed such that there is little overlap in the window of adherence that selects for antiretroviral drug resistance.