The promise of personalized (or precision) treatment for cancer is predicated on the assumption that a comprehensive array of targeted therapeutics will be available in the future. Therefore, there is a substantial unmet need to identify and successfully drug not only the drivers but also the signaling pathways that are critical for the maintenance of the neoplastic phenotype. Furthermore, there is a need for therapeutic depth in these critical pathways to overcome acquired resistance. Similarly, it is important to expand the utility of the therapeutics now in clinical evaluation or approved for treatment of cancer by systematically testing efficacy in preclinical models. By combining these approaches, the promise of precision and personalized medicine can be realized include three main areas of research. The first deals with the mechanism of Notch function. They describe novel components and mechanisms associated with Notch-directed transcriptional regulation. The second area of research describes their ongoing and future efforts in drug discovery and validation. They describe the first Notch-specific small molecule inhibitor targeting the Notch ternary complex and an inhibitor of NACK. The third major focus is on clinical interface research. They have developed patient-derived resources for many distinct tumor types. Using these resources, we have demonstrated a critical role for Notch in esophageal adenocarcinoma. Taken together, their research program is designed to meet the goals of the precision medicine paradigm. That is elucidate basic mechanisms to identify and validate critical targets, the discovery of novel drug candidates and evaluation of these approaches in human cancer models to develop novel precision therapeutic strategies.