c-MYC has a pivotal function in growth control, differentiation and apoptosis, and its abnormal expression is associated with many tumors. Overexpression of c-MYC sensitizes cells to apoptosis by a variety of stimuli. The decision of a cell to undergo apoptosis and how this apoptotic response is regulated by c-MYC depends on the specific cell type and the physiological status of the cell. Multiple cooperating molecular pathways of cell survival and apoptosis determine whether a cell lives or dies, and understanding how c-MYC interfaces with these pathways to influence the survival of cells is important to understand normal and abnormal development, tumor initiation and progression, and response of tumors to different treatment regimens. This article will provide an overview of the function of the tumor suppressor gene product p53 in the c-MYC-mediated apoptotic response and how c-MYC amplifies the intrinsic mitochondrial pathway and triggers and/or amplifies the death receptor pathways. Finally, a model for how deregulated c-MYC prematurely triggers the normal apoptotic response associated with terminal myeloid differentiation while also blocking the differentiation program is presented.