Drug development expenditures continue to escalate, in part reflecting inefficiencies in current drug discovery paradigms. Traditional drug discovery has been dichotomous, focusing either on phenotypic effects of distinct agents in biological systems, without knowledge of respective targets, or on target-based activities of specific molecules in cell-free assays. Driven by advances in biology, engineering, and informatics, new paradigms integrate phenotypic with target-based algorithms into comprehensive, systems-level approaches offering value-added strategies for optimized drug discovery.