This paper addresses some scientific and regulatory perspectives, insightful regulatory experiences, academic views, and current practices pertinent to one-sided and two-sided tests within the framework of clinical trials designed for specific diseases and drugs. It makes compelling points in favor of applying a two-sided test under a wide variety of situations. Additionally, it discusses situations where one may reasonably argue for use of a one-sided test and concludes by suggesting the use of two-sided tests in controversial situations.