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Breaking down the silos between disciplines to accelerate the pace of cancer research is a key paradigm for the Cancer Moonshot. Molecular analyses of cancer biology have tended to segregate between a focus on nucleic acids—DNA, RNA, and their modifications—and a focus on proteins and protein function. Proteogenomics represents a fusion of those two approaches, leveraging the strengths of each to provide a more integrated vision of the flow of information from DNA to RNA to protein and eventually function at the molecular level. Proteogenomic studies have been incorporated into multiple activities associated with the Cancer Moonshot, demonstrating substantial added value. Innovative study designs integrating genomic, transcriptomic, and proteomic data, particularly those using clinically relevant samples and involving clinical trials, are poised to provide new insights regarding cancer risk, progression, and response to therapy.