Human cytomegalovirus (HCMV), a member of an ancient family of viruses (Herpesviridae), has acquired the capacity to maintain a lifelong persistent infection within an immunocompetent host. Since both primary and recurrent infections are generally subclinical, host antiviral immune responses are effective at limiting the pathogenic potential of HCMV. However, the fact that HCMV can persist in the presence of those protective immune responses indicates that host immunity is unable to prevent or eliminate long-term reservoirs of virus. The ability of HCMV to persist has important clinical implications, a fact reflected by the spectrum of pathogenic outcomes observed in those without a fully functional immune system. Recurrence of viral replication or transmission of HCMV from an infected individual to those most susceptible to primary infection during immune suppression, deficiency, or immaturity can lead to multiorgan disease and, sometimes, death. The clinical need for a protective HCMV vaccine has been recognized for decades, but due to a conspiracy of factors, there is no approved vaccine despite intensive investigations to develop one. Animal models of HCMV have been used as systems of discovery and translation to understand viral mechanisms of persistence and pathogenesis, and to test concepts and modalities for the generation of immune responses that protect from primary infection and sequelae. This review summarizes studies in a nonhuman primate model of HCMV involving infection of rhesus macaques (Macaca mulatta) with rhesus cytomegalovirus (RhCMV). The RhCMV model serves as an important complement to those in other animals, particularly small animals, and the lessons learned from RhCMV should have direct clinical relevance to HCMV and the design of protective vaccines.