HIV-1 comprises a collection of closely related, but not identical, viruses or quasispecies. Fitness represents a selective advantage for propagation among populations of organisms competing in a particular environment and is an important characteristic of viruses because of a link between fitness and pathogenesis. Environmental differences based on the type of cell that is targeted for infection or the cell type that produces virus, impact fitness. CD4-expressing cells of lymphocyte or macrophage lineage are the principal host cells for HIV-1, although the milieu in lymphocytes is distinct from the macrophage environment from the perspective of cell half-life and activation, signal transduction and expression of coreceptors, and bioavailability of antiretroviral drugs. Multiple viral determinants, including entry via envelope glycoproteins, replication by reverse transcriptase, and virion maturation by protease activity, contribute to fitness in different cells and provide targets for current antiretroviral therapies. This review focuses on fitness of HIV-1 in macrophages and examines the impact of protease inhibitors on fitness of quasispecies and an unexplained discordance between fitness and pathogenesis.