The clearance of viral infections is reliant on the coordination and balance of inflammatory factors necessary for viral destruction and immunoregulatory mechanisms necessary to prevent host pathology. In the case of persistent viral infections, immunoregulatory pathways prevent the immune response from clearing the virus, resulting in a long-term equilibrium between host and pathogen. Consequently, negative immune regulators are being considered as a therapeutic target to treat persistent and chronic viral infections. In this review, we will highlight the current understanding of the important negative immune regulator interleukin-10 (IL-10) in persistent viral infection. Though its main role for the host is to limit immune-mediated pathology, IL-10 is a multifunctional cytokine that differentially regulates a number of different hematopoietic cell types. IL-10 has been shown to play a role in a number of infectious diseases and many viral pathogens specifically exploit the IL-10 pathway to help evade host immunity. Recent advances have demonstrated that manipulation of IL-10 signaling during persistent viral infection can alter T cell responses in vivo and that this manipulation can lead to the clearance of persistent viral infection. Furthermore, there have been crucial advances in the understanding of factors that induce IL-10. We summarize lessons learned about IL-10 in model organisms and human persistent infections and conclude with the potential use of IL-10 to treat persistent viral infections.