Plant secondary metabolites (PSMs) are non-nutritional components that occur in numerous feed materials and are able to exert toxic effects in animals. The current article aims to summarize innate defense strategies developed by different animal species to avoid excessive exposure to PSMs. These mechanisms include pre-systemic degradation of PSMs by rumen microbiota, the intestinal barrier including efflux transporters of monogastric species, as well as pre-hepatic and intra-hepatic biotransformation processes. These physiological barriers determine systemic exposure and ultimately the dose-dependent adverse effects in the target animal species. Considering the large number of potentially toxic PSMs, which makes an evaluation of all individual PSMs virtually impossible, such a mechanism-oriented approach could improve the predictability of adverse effects and support the interpretation of clinical field observations. Moreover, mechanistic data related to tissue disposition and excretion pathways of PSMs for example into milk, could substantially support the assessment of the risks for consumers of foods derived from PSM-exposed animals.