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The conceptual framework of pragmatism in clinical trials is explored using the American Society of Clinical Oncology's pragmatic, non-randomized, phase II, multi-center basket clinical trial, the Targeted Agent and Profiling Utilization Registry Study (NCT02693535) as a model. The Targeted Agent and Profiling Utilization Registry Study aims to identify signals of drug activity when Food and Drug Administration approved drugs are matched to pre-specified genomic targets in patients with advanced cancer outside of their approved indication(s). The objectives of the study are to generate evidence of potential signals of activity in targeted therapies prescribed in an off-label setting as well as to expose and educate community cancer centers to genomic testing and precision medicine through the study protocol. The principles of pragmatic trial design can be applied across a broad spectrum of evidence-generation strategies, from explanatory trials to real-world evidence studies, and are briefly discussed. American Society of Clinical Oncology's Targeted Agent and Profiling Utilization Registry Study falls closer to the pragmatic end of this spectrum as it seeks to assess the efficacy of Food and Drug Administration approved drugs used outside their approved indications under usual care conditions, yielding results generalizable to the population that would likely receive the intervention in practice, while still adhering to rigorous data quality standards. The Targeted Agent and Profiling Utilization Registry Study's pragmatic objectives, characteristics, strengths, and limitations in its implementation are discussed and demonstrate that a large, multi-center, precision medicine basket trial can be mounted in the context of community practice and can generate clinically useful information with minimal burden to patients and clinical trial sites., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.K.M., E.G-M., and J.K.P. have nothing to disclose. R.L.S. has received institutional support (ASCO) from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Eli Lilly and Company, Merck & Co., Inc., Pfizer, and Seagen for support of the TAPUR Study; R.L.S. has received consulting fees from Cellworks, Scandion Oncology, Bryologyx, Illumina, EQRx, Syapse, and Zephyr AI; R.L.S. has a leadership of fiduciary role for Clarified Precision Medicine and Leap Therapeutics; and R.L.S. has stock or stock options in EQRx, Clarified Precision Medicine and Leap Therapeutics.