At every meal, animals that consume plants are faced with the prospect of being poisoned by naturally occurring toxins, i.e., plant secondary compounds, in plants. Little experimental work exists on the mechanisms that mammals employ to deal with plant toxins or how some species such as the koala or Stephen’s woodrat are capable of specializing on plants that contain high concentrations of toxins. To address this topic, we have been taking a “pharm-ecological” approach that integrates techniques and tools from various disciplines including ecology, behavior, genomics and biochemistry. We have discovered some of the surprising ways in which herbivores cope with toxic diets such as behavioral manipulation, symbioses with gut microbes, and liver enzymes with unexpected biochemical properties. In this presentation, I will highlight some recent results on the role that the microbiome plays in facilitating intake of toxic plants along with the ways in which herbivores behaviorally manipulate food to reduce toxin intake.