Many drugs, or their antecedents, were discovered through observation of their effects on normal or disease physiology. For the past generation, this phenotypic drug discovery approach has been largely supplanted by the powerful but reductionist approach of modulating specific molecular targets of interest. Nevertheless, modern phenotypic drug discovery, which combines the original concept with modern tools and strategies, has re-emerged over the past decade to systematically pursue drug discovery based on therapeutic effects in realistic disease models. Here, we discuss recent successes with this approach, as well as consider ongoing challenges and approaches to address them. We also explore how innovation in this area may fuel the next generation of successful projects.
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