Currently, there are 20 individual antiretroviral drugs and two co-formulation products that are approved by the FDA for the treatment of HIV-infected individuals. It is widely accepted that the selection of an appropriate first-line regimen is critical in assuring durable treatment response. This article reviews the factors that should be considered in the selection of an initial antiretroviral regimen and present the currently available evidence regarding the status of individual antiretroviral agents and treatment strategies relative to these factors.