PROJECT SUMMARY The Proteomics Shared Resource (P-SR) is focused on fostering high-impact cancer-relevant research by providing SCI members with access to state-of-the-art, user-friendly mass spectrometry-based resources and expertise. The P-SR operates 15 mass spectrometer systems that serve ~60 SCI researchers annually. Research support goals are accomplished via the following technical capabilities (1) full-service research partnership from experiment design through sample preparation and mass spectrometric analysis to data analysis; (2) broad-spectrum proteomic support from pilot discovery through complex quantitative assays; (3) customizable quantitative small molecule and clinical scale proteomic assays, taking advantage of modern advances in multiplexing and targeted techniques; (4) intact protein characterization, including antibodies and antibody-drug conjugates; (5) open access walk-up instrumentation and hands-on experience; and (6) online and in-person education, training, and network-building opportunities. These technical capabilities are foundational to numerous scientific areas, such as (1) discovering relevant molecular targets in cancer; (2) providing accurate, orthogonal means of validating research findings from genomic and transcriptomic analyses at the protein level; (3) supporting cancer drug discovery efforts with pharmacokinetics and metabolism analytics; and (4) investigating biological pathways and signaling mechanisms relevant to cancer, both for target and biomarker discovery. Since the last review, the P-SR has continued to acquire new high-end instrumentation, including a Thermo Scientific Q Exactive HF-X and a Waters Xevo TQ-XS. Members of all programs use the P-SR, with the heaviest use coming from the Cancer Biology and Cancer Stem Cells and Cancer Therapeutics programs. In 2020, 41% of users were SCI investigators. The P-SR contributed to 10 cancer-focused publications (5 high-impact). The annual budget of the P-SR is $1,547,560, yet the CCSG request is $70,495. Accordingly, the P-SR leverages extensive institutional support and seeks only 5% from CCSG funds.