The Notch signaling pathway is a highly conserved system that controls embryonic cell fate decisions and the maintenance of adult stem cells through affecting communication between adjacent cells. The pathway is linked to the development of various cancers owing to increased cell proliferation and tumor blood perfusion in addition to inhibition of apoptosis. Pharmaceutical agents that suppress overactive Notch signaling may be of benefit in the treatment of patients with various cancers. These targeted therapies confer several advantages over conventional anticancer therapies including reduced deleterious effects on normal cells. In this review, we explore the rationale for targeting the Notch signaling pathway in cancer along with different investigational strategies designed to block the pathway.