In whole animal-based approaches, phenotypic screening is best exemplified where a substance is evaluated for potential therapeutic benefit across many different types of animal models representing different disease states. Phenotypic screening in animal-based systems utilize model organisms to evaluate the effects of a test agent in fully assembled biological systems.  Example organisms used for high-content screening include the fruit fly (Drosophila melanogaster), zebrafish (Danio rerio) and mice (Mus musculus). In some instances the term phenotypic screening is used to include the serendipitous findings that occur in clinical trial settings particularly when new and unanticipated therapeutic effects of a therapeutic candidate are uncovered.
Screening in model organism offers the advantage of interrogating test agents, or alterations in targets of interest, in the context of fully integrated, assembled, biological systems, providing insights that could otherwise not be obtained in cellular systems.  Some have argued that cellular based systems are unable to adequately model human disease processes that involve many different cell types across many different organ systems and that this type of complexity can only be emulated in model organisms.  The productivity of drug discovery by phenotypic screening in organisms, including serendipitous findings in the clinic, are consistent with this notion.