Progress in understanding the clonal and sub-clonal processes driving tumor evolution, tumor heterogeneity, the mechanisms of therapeutic resistance, and in defining new cancer dependencies have converged to help inform more rational approaches to achieving the development of transformative combination therapeutic regimens in cancer. Nonetheless, examples of highly effective rationally elucidated combinations remain rare and the pre-clinical and clinical development challenges to this goal are substantial. As an example, the emergent role of immunotherapeutics having curative potential has led to tremendous excitement, yet increased complexity. The broad swath of empiric based clinical trials attests to the continued and growing need for improved pre-clinical means by which transformative combinations can be identified. This conference will bring together evolutionary and computational biologists, experts in functional genomics, translational scientists, drug discovery researchers and physician leaders in clinical development. The conference program begins with how evolutionary processes drive the “natural” progression of cancer and how such processes lead to the measured heterogeneous populations of cells resident in all tumors. These two related forces, driven at least in part by ongoing mutational processes, then combine to give rise to therapeutic resistance, which enables researchers to robustly identify mechanisms relevant to humans in pre-clinical models. The deeper understanding of these forces can inform specific combination therapeutics, but combination hypotheses are now being discovered though genome-scale functional screening approaches (e.g. CRISPR, shRNA). Speakers have been invited to discuss the studies which are now taking place in both the targeted and immuno-oncology (I/O) therapeutic fields. These talks filter into sessions on understanding how I/O and targeted therapeutics are similar or distinct and to seek the lessons from the clinical trial outputs in the I/O field that will emerge over the next year. Finally, clinical development paradigms for more rapidly testing and developing combinations will be covered during the conference.