Sequences of the gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV) were first identified in tissue samples from human prostate tumors. It was subsequently isolated from the peripheral blood mononuclear cells of patients with chronic fatigue syndrome (CFS). However, several follow-up studies were unable to duplicate the results. Immune dysfunction caused by XMRV has been suggested to play a role in the pathogenesis of CFS. Differences in the diagnosis of patients may be a factor in the negative studies, and resolving these discrepancies has crucial implications in the diagnosis, prevention, and treatment of patients with CFS. Currently approved antiretroviral drugs have been found to inhibit XMRV replication in vitro but should not be given to patients with CFS at present until further data demonstrate a clear benefit. Screening donated blood and organs to prevent transmission may become an important public health issue.