Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus (GHV) that causes acute infection and establishes life-long latency. EBV is associated with the development of B-cell lymphoproliferative disorders, several malignant cancers, the syndrome of infectious mononucleosis, and chronic interstitial lung disease. Although the molecular biology of EBV has been characterized extensively, the associated disease conditions and their pathogenesis are difficult to study in human populations because of variation in human environments and genetics, the well-documented effect of stressors on pathogenesis, and the chronic and latent properties of the virus. GHV are highly species-specific, and suitable animal models for EBV are not available. However, in 1980, a murine gammaherpesvirus (MuGHV, also known as MHV68 and gammaHV68) was identified as a natural pathogen of bank voles and wood mice. Experimental MuGHV infections in laboratory mice share many features of EBV infections in humans, including facets of the clinical human syndrome known as infectious mononucleosis. These features make MuGHV a valuable experimental model for studying the pathophysiology of a GHV in a natural host.