Notch signaling controls cell fate decisions including during development and stem cell renewal and differentiation in many postnatal tissues. Increasing evidence suggests that the Notch signaling network is frequently deregulated in human malignancies and that genetic or pharmacological manipulation of Notch signaling is a novel potential strategy for the treatment of human neoplasms. This review article summarizes the most recent preclinical and clinical evidence linking Notch signaling to cancer, delineates questions that remain unanswered and explores potential biopharmacological strategies to manipulate Notch signaling in vivo.