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There is a growing realization that the rational design and optimization of combination therapies is critical to achieving practical successes in the field of Oncology. The heterogeneous and evolving nature of tumors in the clinical setting serves to readily defeat single-agent targeted therapies. The traditional paradigm of selecting combinations based on synergy in preclinical experiments sidesteps the fundamental challenge of Oncology combination development- will the combination possess a broader therapeutic window than each drug alone? In this conference, we will discuss ways in which this critical challenge can be addressed in a targeted manner.