Today, most hospitals have implemented regulatory programs designed to curtail the antimicrobial misuse that has fueled resistance. In this paper, I trace the history of resistance and efforts to mitigate antibiotic overuse in the hospital. Medical investigators in the 1950s argued that the difficulties posed by resistant bacteria in the hospital were even more worrisome than the problems that antibiotics were intended to solve. These investigators sought to reform physician habits that they believed, left unchecked, would accelerate resistance and hasten the end of the antibiotic era. When their methods of education failed to change physician’s prescribing habits voluntarily, external restrictions were imposed. Today’s antimicrobial stewardship programs represent the newest version of a series of efforts that began in the mid-twentieth century to reform antibiotic misuse and to control resistant microbes in the hospital.