The diverse roles that Notch signals play during the development and maintenance of normal tissues are recapitulated in different forms of cancer. Depending on the tumor type, Notch can variously promote or limit tumor growth through either cell autonomous or cell non-autonomous effects on differentiation, cellular metabolism, cell cycle progression, angiogenesis, and possibly self-renewal and immune function. Of particular interest, recent findings indicate that a high fraction of T-cell acute lymphoblastic leukemias and lymphomas have activating mutations in the Notch1 receptor, and that Notch signaling might have a role in the maintenance of normal and malignant stem cells.