ABSTRACT The USC Norris Comprehensive Cancer Center first participated in the research activities of SWOG in 1987 and was initially funded in 1992. This five-year grant cycle has had increased administrative and academic participation, with maintenance of high clinical and correlative trial entry, commensurate with available SWOG funding and added resources from USC. The major emphases of the USC team are (a) to provide leadership across the NTCN to design and efficiently perform clinical trials evaluating the safety and efficacy of novel regimens or modifications of existing regimens; (b) to provide leadership in biomarker development and in integration of new technologies into NCTN trials, taking advantage of a systematic approach to collection, processing, and storage of blood, normal tissue, fresh or frozen tumor tissue, and other relevant biologic samples for molecular and pharmacologic studies; and (c) to evaluate cancer treatment regimens in special patient populations, such as rare cancers, the elderly and ethnic minorities. USC investigators have not only contributed extensively to SWOG trials but have demonstrated administrative/academic leadership, facilitating the translation of specific themes of investigation to SWOG. Recent NCTN trials such as SWOG/ALLIANCE 80405 and S1401 characterizing metastatic colorectal and prostate cancer has significant increased the understanding of molecular subtyping and characterization of both cancers integrating cutting edge technologies including NGS testing and single cell molecular classification. USC UG1 members are playing an active role in NCI task forces and steering committees. As part of its dedication to cancer clinical research, USC has been successful in mentoring young investigators through the UM1 Career Development Awards, Project Team Memberships and SWOG Young Investigator Awards. USC has expanded its institutional training and mentoring capabilities. Lastly, as a Network Lead Academic Participating Site, USC will continue to bring unique strengths to the NCI National Clinical Trials Network thanks to its strength in recruitment of minorities to clinical trials, accrual to rare cancers such as biliary and bladder cancers, and a well- developed clinical research infrastructure.