The story of Rapamune (sirolimus, rapamycin) began with the isolation of an antibiotic from a soil sample sent to Ayerst Laboratories in Montreal. More than 25 years later, sirolimus was approved for use by transplant physicians in the United States. Development programs for new drugs for transplantation face significant challenges. Four key challenges were critical to the development of sirolimus as a drug for transplantation: First, sirolimus was not intended to be an antirejection agent. Second, sirolimus was not easy to make or purify into a palatable substance for human use and the development of a pharmaceutical form was an important and critical hurdle. Third, sirolimus showed potent antirejection activity when tested in de novo allograft recipients, but the development program required careful attention to its optimal use in multidrug transplant regimens. Fourth, the clinical program approved in the United States was rejected in Europe, and it was only with additional studies and a unique appeal process that sirolimus became available in Europe. Currently, sirolimus (Rapamune) is available throughout most of the world except in Japan, having achieved regulatory approvals in North America, Europe, the Middle East, Latin America, and Asia. Although sirolimus failed in its original role as an antifungal agent, it ultimately succeeded as an antirejection drug. Today, sirolimus holds additional promise both as a drug useful for the prevention of restenosis after coronary angioplasty and as an antitumor agent.