Deciding that a drug, biological product, or medical device works involves uncertainty, and the generation and interpretation of medical evidence evolves over time. Evaluating the potential benefit of therapeutic interventions has historically involved individual case reports, clinical reasoning, and other strategies—with the randomized, controlled trial (RCT) notably becoming the archetype methodology for evaluating the effectiveness of new interventions as of the mid-20^th century. RCTs evolved in various ways during the late 20^th century, both within the practice of medicine as well as from the perspective of regulatory agencies, including the U.S. Food and Drug Administration. Although dominant for decades, the RCT-based paradigm is now embedded in a new landscape of methods and concepts that is changing the way we view causal inference as well as the evidence required for regulatory and clinical decision-making. Specifically, technological advances that provide electronic access to massive volumes of more detailed healthcare data (“big data”) are being used to evaluate therapeutic effectiveness, with or without the conduct of an RCT; such data are also linked to the terms “precision” (or “personalized”) medicine. This session will first describe how the ascendancy of the RCT led to emergence of the Evidence-Based Medicine movement in the 1990s, promoting RCTs as the optimal source of medical knowledge for research, drug development, teaching, and clinical care; big data and precision medicine will also be discussed. Next, the session will focus in detail on the evolution of RCTs themselves and the role they play in decision-making by regulatory agencies when evaluating potential new drugs. Finally, the session will examine the impact of Congressional legislation, specifically the real-world evidence (RWE) provision of the 21^st Century Cures Act in 2016, which defined RWE as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” Medical researchers, regulators, clinicians, and patients should understand the shifting ways in which the methods of science are brought to bear in dealing with uncertain evidence of a drug’s effectiveness. The scientific and regulatory history of medical evidence offers insights into forces that generate accepted medical knowledge.