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Endometrial cancers (ECs) arise from the inner epithelial lining of the uterus. At diagnosis, the majority of ECs are carcinomas of endometrioid, serous, or clear cell histologies, or an admixture of at least two of these histological subtypes. Serous and clear ECs are rare at presentation but contribute disproportionately to mortality from EC. Thus, there is an acute need for novel therapeutic approaches to treat serous and clear cell ECs. Small molecule inhibitors directed against tyrosine kinases have shown clinical efficacy in other types of cancer in which the target kinase is mutationally activated. Here, we used Sanger sequencing to systematically search for somatic mutations within 527 exons that encode the catalytic domains of 85 tyrosine kinases from 23 serous, 10 clear cell, and 5 mixed histology ECs. For mutated genes, we extended the screen to another 73 ECs (21 serous, 10 clear cell, 42 endometrioid). Genes that were mutated in both the primary and secondary screens were resequenced in a tertiary screen to search for mutations in all coding exons among the entire panel of 111 endometrial tumors. Overall, we uncovered nonsynonymous somatic mutations of ACK1, DDR1, and KDR in 5.4%, 3.6%, and 1% of ECs. Serous tumors had mutated ACK1, DDR1 and KDR in 2.3%, 4.5%, and 2.3% of cases. Clear cell tumors had mutated ACK1 in 5% of cases. Endometrioid tumors had mutated DDR1 in 2.3% of cases. Immunoblotting confirmed that ACK1 and DDR1 are endogenously expressed in endometrial cancer cell-lines. Eighty-seven percent (7 of 8) of ACK1 mutations and 50% (2 of 4) of DDR1 mutations are predicted to impact protein function. To our knowledge this is the first report of ACK1 and DDR1 mutations in endometrial cancer. Our findings warrant future studies to determine whether the ACK1 and DDR1 mutations uncovered here are pathogenic. Citation Format: Meghan L. Rudd, Hassan Mohamed, Jessica C. Price, Mary Ellen Urick, Andrea J. O'Hara, Matthieu Le Gallo, NISC Comparative Sequencing Program, Pedro Cruz, Suiyuan Zhang, James Mullikin, Maria J. Merino, Daphne W. Bell. Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5312. doi:10.1158/1538-7445.AM2013-5312