► We present new findings linking activating mutations in Notch1 to B cell neoplasms. ► We discuss the discovery of Notch gene rearrangements in breast cancer. ► We review the discovery of loss-of-function mutations in Notch receptors in squamous cell carcinoma. Recent deep sequencing of cancer genomes has produced an explosion of new data implicating Notch signaling in several human cancers. Unlike most other pathways, these data indicate that Notch signaling can be either oncogenic or tumor suppressive, depending on the cellular context. In some instances, these relationships were predicted from mouse models or presaged by developmental roles for Notch, but in other cases were unanticipated. This review discusses the pathogenic and translational significance of these new findings.