Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC-driven tumors. We also highlight biological differences within specific tumor types that are driven by the different MYC proteins. N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes.