GW501516 was initially discovered during a research collaboration between GSK and Ligand Pharmaceuticals that began in 1992. The discovery of the compound was published in a 2001 issue of PNAS. Oliver et al. reported that they used "combinatorial chemistry and structure-based drug design" to develop it. One of the authors was the son of Leo Sternbach who discovered benzodiazepines in the 1960s.
R & D Focus Drug News reported that GSK began phase I trials of the compound for the treatment of hyperlipidemia in 2000 followed by phase I/II in 2002. In 2003, Ligand Pharmaceuticals earned a $1 million payment as a result of GSK continuing phase I development.
By 2007, GW501516 had completed two phase II clinical studies and other studies relating to obesity, diabetes, dyslipidemia and cardiovascular disease, but GSK abandoned further development of the drug in 2007 for reasons which were not disclosed at the time. It later emerged that the drug was discontinued because animal testing showed that the drug caused cancer to develop rapidly in several organs, at dosages of 3 mg/kg/day in both mice and rats.
Ronald M. Evans's laboratory purchased a sample of GW501516 and gave mice a much higher dose than had been used in GSK's experiments; they found that the compound dramatically increased the physical performance of the mice. The work was published in 2007 in Cell and was widely reported in the popular press including The New York Times and The Wall Street Journal.
Concerns were raised prior to the 2008 Beijing Olympics that GW501516 could be used by athletes as an ergogenic performance-enhancing drug that was not currently controlled by regulations or detected by standard tests. One of the main researchers from the study on enhanced endurance consequently developed a urine test to detect the drug, and made it available to the International Olympic Committee. The World Anti-Doping Agency (WADA) developed a test for GW501516 and other related PPARδ modulators, and added such drugs to the prohibited list in 2009.
GW501516 has been promoted on bodybuilding and athletics websites and by 2011 had already been available for some time on the black market. In 2011, it was reported to cost $1,000 for 10 g. In 2012, WADA recategorised GW501516 from a gene doping compound to a "hormone and metabolic modulator".
In 2013, WADA took the rare step of warning potential users of the compound of the possible health risks, stating that "clinical approval has not, and will not be given for this substance"; the New Scientist attributed the warning to the risks of the drug causing cancer.
A number of athletes have tested positive for GW501516. At the Vuelta Ciclista a Costa Rica in December 2012, four Costa Rican riders tested positive for GW501516. Three of them received two-year suspensions, while the fourth received 12 years as it was his second doping violation. In April 2013, Russian cyclist Valery Kaykov was suspended by cycling's governing body UCI after having tested positive for GW501516. Kaykov's team RusVelo dismissed him immediately and in May 2013, Venezuelan Miguel Ubeto was provisionally suspended by the Lampre team. In February 2014, Russian race walker Elena Lashmanova tested positive for GW501516. In April 2019, heavyweight boxer Jarrell Miller tested positive for GW501516 which caused his challenge for Anthony Joshua's World Heavyweight titles to be cancelled.