The Notch signaling pathway is a highly conserved developmental pathway, which plays a critical role in cell-fate decision, tissue patterning and morphogenesis. There is increasing evidence that this pathway is dysregulated in a variety of malignancies, and can behave as either an oncogene or a tumor suppressor depending upon cell context. This review highlights the current evidence for aberration of the Notch signaling pathway in a wide range of tumors from hematological cancers, such as leukemia and lymphoma through to skin, breast, lung, pancreas, colon and brain tumors. It proposes that the Notch signaling pathway may represent novel therapeutic targets and will be a welcome asset to the cancer therapeutic arena.