Research is underway to uncover new biomarkers and ways to explore their application in cancer detection and treatment. These new developments require novel approaches to incorporate such information for therapy evaluation, leading to a new generation of clinical trials that modernize the approach to monitor safety and efficacy. This talk re-visits some of the basic components of clinical trial design and analyses within the context of timely areas of drug discovery. In specific, cancer therapies that are immune-based, stem cell targeted, and and epigenetic-based, are discussed in terms of the impact of advances made in cancer biology and technology on their clinical trial design and analyses. In each case, a clear need for multiple endpoints is presented and the challenges in devising and testing for such endpoints to monitor toxicity and evaluate efficacy are discussed.