PROJECT SUMMARY/ABSTRACT The Laura and Isaac Perlmutter Cancer Center (PCC) is a university-based matrix center that oversees all cancer research and care in the NYU Langone Health system (NYULH) and affiliated units at New York University/NYU. We serve a large catchment area that encompasses most of Manhattan, and all of Brooklyn, Queens, and Long Island and is home to 9.1 million highly diverse residents. Our 195 Members and 68 Associate Members belong to 17 NYU Grossman School of Medicine (NYUGSoM) departments or 5 other NYU colleges/schools. Members have active, peer-reviewed funding in basic, translational, clinical, and/or population research or lead clinical trials. Associate Members direct shared resources, treat and accrue cancer patients to (but do not lead) trials, or have scientific interests related to cancer, but no cancer-related funding. PCC laboratory and population science research takes place at the NYULH main campus, the adjacent Alexandria Buildings, other units of NYU, and the New York Genome Center (NYGC). Guided by our new Strategic Plan, research is organized into three transdisciplinary, bench to bedside to bench Programs (Cancer Genome Dynamics, Cancer Cell Biology, Tumor Immunology) and one population science Program (Epidemiology and Cancer Control). These Program all address the major cancer burdens and/or disparities in our catchment area. Members make extensive use of 11 cutting edge, well-supported Shared Resources. Current NCI funding is $29.5M, a >70% increase since 2018; total peer-reviewed cancer funding is $75M (50% increase), and total cancer-relevant funding is $90M (42% increase). Team science is also strong, with 22% intra-programmatic, 14% inter-programmatic, and 49% inter-institutional (with other NCI-CCs) publications. These studies are highly influential: 33% are in journals with IF>10 and ~20% in those with IF>15. Over the past 5 years, PCC laboratory scientists have made paradigm-changing discoveries in cancer epigenetics, signal transduction, especially RAS/ERK pathway biology, metabolism, and immunology. Clinical trial activity has increased in quality, quantity, and impact. Our clinical researchers helped change practice for lung and bladder cancer, melanoma, childhood leukemia, and lymphoma, and PCC population research informed public policies on tobacco control, obesity, infection-related cancers, and environmental pollutants. We enter our 43rd year more committed than ever to “bringing visionary thinking and compassionate care to the science of treating cancer, with the goal of curing cancer in our lifetime”.