Successful pathogen clearance depends on a finely orchestrated equilibrium between inflammatory immune responses and immunoregulatory mechanisms that limit collateral tissue damage. The cytokine interleukin 10 (IL-10) has been shown to play a critical role in this balance in numerous infectious diseases. Studies in animal models have revealed that IL-10 gene-knockout or signaling blockade can enhance resistance to pathogens, and substantially facilitate viral clearance. These same interventions in other infections however, result in more severe disease due to the inability of the immune system to adequately contain the pathogen load, and to control immune-mediate damage. This IL-10-regulated balance is also apparent in human infectious diseases. This review summarizes evidence that IL-10 impacts many aspects of HIV pathogenesis, including the regulation of HIV-specific CD4 and CD8 T cell functions, as well as modulation of HIV-replication in PBMC subsets. Genetic polymorphisms in the IL-10 gene promoter that lead to decreased IL-10 expression have been associated with more rapid disease progression in late stages of HIV infection, suggesting that the anti-inflammatory effects of IL-10 may be protective in the setting of chronic immune activation. We conclude with a discussion of important questions remaining, and the potential for therapeutic intervention based on manipulation of the IL-10 pathway.