In this article we explore the different trajectories of this one drug, phenylbutazone, across two species, humans and horses in the period 1950–2000. The essay begins by following the introduction of the drug into human medicine in the early 1950s. It promised to be a less costly alternative to cortisone, one of the “wonder drugs” of the era, in the treatment of rheumatic conditions. Both drugs appeared to offer symptomatic relief rather than a cure, and did so with the risk of side effects, which with phenylbutazone were potentially so severe that it was eventually banned from human use, for all but a few diseases, in the early 1980s. Phenylbutazone had been used with other animals for many years without the same issues, but in the 1980s its uses in veterinary medicine, especially in horses, came under increased scrutiny, but for quite different reasons. The focus was primarily the equity, economics, and ethics of competition in equine sports, with differences in cross-species biology and medicine playing a secondary role. The story of phenylbutazone, a single drug, shows how the different biologies and social roles of its human/animal subjects resulted in very different and changing uses. While the drug had a seemingly common impact on pain and inflammation, there were inter-species differences in the drug’s metabolism, the conditions treated, dosages, and, crucially, in intended clinical outcomes and perceptions of its benefits and risks.