Observational data linking physical activity and exercise exposure with reduced risk of either development or progression of cancer have fueled interest in the initiation of large-scale definitive trials to test the association of exercise therapy with disease outcomes. However, several major knowledge gaps impede the rational and optimal design of such trials.Critical requirements underpinning the success of several recent contemporary anticancer agents have included adequate demonstration of antitumor activity (in phase 1/2 trials) as well as identification of essential prerequisites (eg, biologically effective dose and predictors of response) permitting optimal design of definitive trials. The existing evidence base investigating exercise as a candidate anticancer preventive or treatment strategy is predominantly confined to observational data, which have several inherent limitations. Consequently, the antitumor activity of exercise remains unclear and, perhaps more important, such data are not sufficient to accurately derive the exercise dose, prescription regimen, or patients most likely to benefit from exercise. In adherence with translational frameworks for lifestyle therapy development, the need for early phase 1/2-equivalent trials to fill current knowledge gaps to optimize the development and potential efficacy of exercise therapy is highlighted.Exercise therapy has significant promise to be an efficacious and cost-effective therapy to improve cancer outcomes, with few toxic effects. Although most nontraditional therapies in cancer prevention and prognosis fail in definitive trials, these failures provide critical lessons for the continued development of exercise as a candidate anticancer therapy.