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Phenotypic screens in model organisms provide an in vivo, intact biological system to reveal both molecular and systems level insights into normal and disease states, and drug or treatment effects. Despite a rich history of model organism use in scientific and drug discovery, only recently has the convergence of new technologies made high throughput screens feasible with model organisms. In this chapter, we first discuss the utility of phenotypic screens, their historical challenges, and the approaches and considerations for performing a screen. We then discuss powerful new genetic and computational engineering technologies, and how these can enable more data rich, complex and detailed screens that incorporate behavioral and physiological modalities, and the key technical considerations for analyzing such large scale data to yield meaningful, actionable results. We share a new paradigm for phenotypic screening, which will open new avenues for discovery in basic science and drug development.

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