Highly active antiretroviral therapy (HAART)^,, has dramatically decreased mortality from HIV-1 infection and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication^,,,,,, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines^, are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.