Abstract The MYC oncogene is frequently overexpressed in human cancers. MYC can transcriptionally and translationally regulate the expression of thousands of genes. However, it was unclear which specific genes are responsible for MYC to maintain a neoplastic state. The microRNA cluster miR-17-92 is a major MYC target gene known to regulate proliferation, survival, and angiogenesis, which are several of the key phenotypes associated with MYC oncogene addiction. The resemblance of biological functions between MYC and miR-17-92 thus evoked the hypothesis that miR-17-92 is causally responsible for at least part of the mechanism by which MYC maintains a neoplastic state. We have found that miR-17-92 regulates multiple histone modifiers, such as Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim, to maintain autonomous proliferation, survival, and self-renewal of MYC-driven tumors. Conversely, MYC inactivation downregulates the expression of miR-17-92 and results in the loss of neoplastic features as a consequence of restoration of senescence, apoptosis, and differentiation. Thus, the expression of miR-17-92 can dictate the cellular fates of MYC-driven tumors between survival versus apoptosis and proliferation versus senescence. Our findings provide a mechanistic insight into why tumors are dependent on or addicted to MYC. Citation Format: Yulin Li, Peter S. Choi, Stephanie C. Casey, David L. Dill, Dean W. Felsher. miR-17-92 mediates MYC oncogene addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR13.