Abstract Premature delivery has long been a major problem in obstetrics. Increased perinatal morbidity and mortality as well as substantial health care costs, both short and long term, have driven the efforts to combat this complication. While multiple agents have been studied over the last 70 years leading to hundreds of publications and involving tens of thousands of patients, no benefit to neonates has been demonstrated to date for any of these agents. Nonetheless, clinical use of reputed “tocolytic agents” has been incorporated in both the medical and lay literature as the standard of care. Unfortunately, use of medications without evidence of efficacy has only added to health care costs, caused harm in some cases, and rendered necessary placebo‐controlled trials difficult if not impossible. This clinical opinion will consider the stories of various attempts to identify an effective medication in order to demonstrate the shortcomings of the current approach to the study of possible tocolytic agents and suggest changes that may lead to a more rational approach to drug development.