Throughout our life, long-lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self-renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG-001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI-724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.