Leukemias expressing activated tyrosine kinases (TKs) BCR/ABL and FLT3/ITD activate signaling pathways that lead to increased survival and proliferation. Expression of these oncogenes also results in increased genomic instability, evidenced by altered double-strand break (DSB) repair that may result in increased genomic changes, leading to disease progression and resistance to therapy. There are two main pathways for DSB repair: the error-free homologous recombination (HR) pathway and the error-prone non-homologous end-joining (NHEJ) pathway. In BCR/ABL- and FLT3/ITD-positive leukemias, HR is characterized by increased single base-pair s and NHEJ shifts to a highly error-prone alternative pathway. Increased expression of transcripts encoded by key gene components of these repair mechanisms and translated proteins are involved in generating increased errors. Increased expression of HR component RAD51 leads to unfaithful repair. For NHEJ, components of the classical pathway (C-NHEJ) are decreased, and in turn, levels of ALT-NHEJ factor DNA ligase IIIα (LIG3) are increased, resulting in increased frequency of large DNA deletions. Evidence suggests that c-MYC is a good candidate for transcriptional regulation of both RAD51 and LIG3 in TK-activated leukemias: Expression of c-MYC is increased in TK-activated leukemias, putative binding sites for c-MYC exist in the promoters of these genes, and c-MYC regulates RAD51 expression in prostate cancer. In this study we tested the hypothesis that c-MYC plays a role in the transcriptional regulation and/or activity of RAD51 and LIG3. We demonstrated that (1) chemical and siRNA inhibition of c-MYC results in downregulation of LIG3 and RAD51 in FLT3/ITD- and BCR/ABL-positive cells; (2) downregulation of RAD51, but not LIG3, is attributed to c-MYC-mediated block of entry into S-phase; (3) c-MYC binds to the promoter of LIG3, and (4) importantly, c-MYC downregulation results in functional consequences for both HR and NHEJ: RAD51 foci formation is inhibited following exposure to ionizing radiation, and decreased LIG3 results in increased NHEJ repair fidelity. Based on these findings, we conclude that c-MYC plays an important role in the induction of genomic instability through regulation of double-strand break repair pathways that lead to increased errors. These results merit further exploration of mechanisms through which c-MYC functions in this process.