The Yale Cancer Center (YCC) was designated as an NCI Comprehensive Cancer Center in 1974. YCC has elected to profoundly alter its structure to better facilitate clinical translation of its abundant scientific strengths. A particularly important component, taken in consultation with the NCI, was relocation of operational control of Medical Oncology to YCC, to augment Center influence over the Clinical Trials Program. An administrative 3-year extension from the NCI enabled these changes. The new Director, Richard Edelson, an accomplished translational scientist, has led the Center since these pivotal changes were initiated in 2003. Over $68 million of institutional support permitted YCC to enhance facilities and recruit 60 external faculty members, including leaders of 5 of the 8 Research Programs, 6 of the 11 interdisciplinary cancer disease site teams and both the Clinical Research Services Core and Protocol Review Committee. Strategic scientific recruitments include Joseph Schlesinger (pioneer in the design of inhibitors of receptor tyrosine kinases and now Co-Leader of the Signal Transduction Program) and Jeffrey Sklar (a leading innovator in molecular diagnosis of cancer and now Co-Leader of the Gene Regulation and Functional Genomics Program). Preserving continuity by reappointing the Deputy Director, the Director appointed new Associate Directors of Basic and Clinical Sciences. All Research Programs now thematically stress mechanistic themes, and the Clinical Division has been organized around the three main cancer treatment modalities (small molecules/anticancer agents, radiation therapy, and biological/ immunological agents), rather than being confined to single disease sites. Due to these collective YCC structural and functional changes, the number of investigator initiated clinical trials, based on YCC science, have dramatically increased. Construction has begun on a $460M new Clinical Cancer Tower, proximal to the YCC scientific laboratories. The 210 YCC members come from 27 Yale Departments and 4 Schools. Since the last CCSG submission, total peer-reviewed, annual direct costs of cancer-relevant research support increased by 42%, from $43 million to $62 million, inclusive of $15.3 million from the NCI. Integration of the new scientific and clinical investigators has permitted the YCC to target 8 sets of grouped research projects for focused development. Last approved in 1998, YCC continues to satisfy guidelines for Comprehensiveness. Based on the NCI total cost funding base of $25.6 million, YCC is requesting a budget of $3.8 million in total costs.