Notch signalling is a conserved developmental pathway involved, inter alia, in cell-fate decision, morphogenesis and tissue patterning. Extensive research has linked this pathways with a variety of malignancies, cancer stem cell renewal, induction of epithelial-to-mesenchymal transition and tumor angiogenesis. These data indicate that Notch can act as both a tumor suppressor and an oncoprotein, depending upon cellular context and identify it as a potential therapeutic target in cancer treatment. This review discusses the implications of Notch in a number of hematologic and solid malignancies and some of the currently available inhibitors developed against this pathway as potential cancer therapeutics.