Patients, clinicians, payers, and policymakers face an environment of significant evidentiary uncertainty as they attempt to achieve maximum value, or the greatest level of benefit possible at a given level of cost in their respective health care decisions. This is particularly true in the area of oncology, for which published evidence from clinical trials is often incongruent with real-world patient care, and a substantial portion of clinical use is for off-label indications that have not been systematically evaluated. It is this uncertainty in the knowledge of the clinical harms and benefits associated with oncology treatments that prevents postregulatory decision makers from making accurate assessments of the value of these treatments. Because of the incentives inherent in the clinical research enterprise, randomized control trials (RCTs) are designed for the specific purpose of regulatory approval and maximizing market penetration. The pursuit of these goals results in RCT study designs that achieve maximal internal validity at the expense of generalizability to diverse real-world patient populations that may have significant comorbidities and other clinically mitigating factors. As such, systematic reviews for the purposes of coverage and treatment decisions often find relevant and high-quality evidence to be limited or nonexistent. For a number of reasons, including frequent off-label use of medications and the expedited approval process for cancer drugs by the U.S. Food and Drug Administration, this situation is exacerbated in the area of oncology. This paper investigates the convergence of incentives and circumstances that lead to widespread uncertainty in oncology and proposes new paradigms for clinical research, including pragmatic clinical trials, methodological guidance, and coverage with evidence development. Each of these initiatives would support the design of clinical research that is more informative for postregulatory decision makers, and would therefore reduce uncertainty and provide greater confidence in conclusions about the value of these treatments.