Cellular apoptotic pathways converge on the activation of procaspase-3, resulting in the production of active caspase-3. Caspase-3 catalyzes the hydrolysis of hundreds of cellular substrates and, once activated, rapidly induces apoptotic cell death. In 2006 we reported PAC-1 as the first small molecule to directly activate procaspase-3, and since then we have defined the mechanism by which this compound activates procaspase-3, and have synthesized hundreds of derivatives. Given that procaspase-3 levels are elevated in many tumor tissues, PAC-1 and related compounds have considerable potential for treatment of cancer. Toward this end, PAC-1 and its derivative S-PAC-1 have been evaluated in canine cancer patients, and PAC-1 is now being administered to human cancer patients through a Phase I clinical trial at the University of Illinois Cancer Center in Chicago and at Johns Hopkins University. See more information at clinicaltrials.gov.