Abstract cBioPortal for Cancer Genomics is an open-source platform for interactive, exploratory analysis of large-scale cancer genomics data sets. cBioPortal provides a user-friendly interface that integrates genomic and clinical data, and provides a suite of visualizations and analyses, including OncoPrints, mutation “lollipop” plots, variant interpretation, group comparison, survival analysis, expression correlation analysis, alteration enrichment analysis, cohort and patient-level visualization. cBioPortal also integrates external tools including CIViC, Cancer Digital Slide Archive, Next-Generation Clustered Heat Map, IGV and Bioconductor to facilitate interpretation. The public site (https://www.cbioportal.org) is accessed by ~35,000 unique visitors each month and hosts data from >325 studies spanning individual labs and large consortia. In addition, >67 instances of cBioPortal are installed at academic institutions and pharmaceutical/biotechnology companies worldwide. In 2021 we added data from 32 studies, totaling >24,000 samples, to the public site. All data is also available in the cBioPortal Datahub: https://github.com/cBioPortal/datahub/. We also host a dedicated instance for AACR Project GENIE, enabling access to the GENIE cohort of >135,000 clinically sequenced samples from 19 institutions (https://genie.cbioportal.org). In addition, the GENIE Biopharma Collaborative (BPC) enables the collection of comprehensive clinical annotations, including response, outcome, and treatment histories. The first BPC release contains data from >1,800 non-small cell lung cancer samples and will be released in early 2022. The growing GENIE cohort and the BPC clinical data have driven a number of recent developments, including performance improvements (the load time for the GENIE cohort was reduced from minutes to seconds). To leverage the BPC clinical data, we enabled sample selection based on treatment status, extended support for outcome analysis, and enhanced the patient timeline representation to incorporate response data. Additional development work has focused on improvements to variant interpretation, enhancements to the Mutations tab, and support for novel molecular assays via the ‘generic assay’ data type. Documentation on these new features and many others is available at https://www.cbioportal.org/news. cBioPortal is fully open source (https://github.com/cBioPortal/) under a GNU Affero GPL license. Development is a collaborative effort among groups at Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Children’s Hospital of Philadelphia, Princess Margaret Cancer Centre, Bilkent University and The Hyve. We welcome open source contributions from others in the cancer research community. Citation Format: Jianjiong Gao, Tali Mazor, Ino de Bruijn, Adam Abeshouse, Diana Baiceanu, Ziya Erkoc, Elena Garcia Lara, Benjamin Gross, David M. Higgins, Prasanna K. Jagannathan, Priti Kumari, Ritika Kundra, Xiang Li, James Lindsay, Aaron Lisman, Divya Madala, Ramyasree Madupuri, Angelica Ochoa, Oleguer Plantalech, Sander Rodenburg, Baby A. Satravada, Robert Sheridan, Lucas Sikina, Jessica Singh, S. Onur Sumer, Yichao Sun, Pim van Nierop, Avery Wang, Manda Wilson, Hongxin Zhang, Gaofei Zhao, Sjoerd van Hagen, Kees van Bochove, Ugur Dogrusoz, Allison Heath, Adam Resnick, Trevor J. Pugh, Chris Sander, Ethan Cerami, Nikolaus Schultz. cBioPortal for cancer genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1155.