In 2006, a new retrovirus was isolated from prostate cancer patient tissue. Named xenotropic murine leukemia virus-related virus (XMRV), this was potentially the third class of retrovirus to be pathogenic in humans. XMRV made a more dramatic impact on the wider scientific community, and indeed the media, in 2009 when it was reported to be present in a remarkably high proportion of patients with chronic fatigue syndrome as well as a significant, albeit smaller, proportion of healthy controls. The apparent strong link to disease and the fear of a previously unknown retrovirus circulating in the general population lead to a surge in XMRV research. Subsequent studies failed to find an association of XMRV with disease and, in most cases, failed to find the virus in human samples. In 2011, the case against XMRV and human disease strengthened, ending with several decisive publications revealing the origin of the virus and demonstrating contamination of samples. In this review, we outline the passage of research on XMRV and its potential association with disease from its isolation to the present day, where we find ourselves at the end of a turbulent story.