Xenotropic-murine-leukemia-virus-related virus (XMRV) was the first gammaretrovirus to be reported in humans. The sequence similarity between XMRV and murine leukemia viruses (MLVs) was consistent with an origin of XMRV from one or more MLVs present as endogenous proviruses in mouse genomes. Here, we review the relationship of the human and mouse virus isolates and discuss the potential complications associated with the detection of MLV-like sequences from clinical samples.