A diverse range of fauna could be exposed to active pharmaceutical ingredients (APIs) via diet, dermal absorption or bioconcentration. Low level exposures of free-ranging wildlife to APIs has only been demonstrated for a few pathways (e.g., ingestion of fish in estuaries by piscivorous birds), and many remain hypothetical (e.g., ingestion of invertebrates in sludge amended fields by terrestrial vertebrates). Our understanding of API dose-response relationships in wildlife have only been assessed for endocrine disrupting compounds and a few veterinary therapeutics. Drug specific responses at various levels of biological organization are poorly characterized for nearly all wildlife species, and thus our understanding of risk is limited. There is interest in using a read-across approach to fill knowledge gaps for risk. This approach, using data collected in laboratory mammals and humans, would enable predictions for likelihood of adverse effects in wildlife. Given the great diversities in physiologies among species, a combination of in vivo, in vitro and in silico approaches will be required to fill the knowledge gaps for exposure, hazard and risk.