Advances in analytical chemistry techniques have supported identification of various emerging contaminants at ng/L levels in the environment, including human pharmaceuticals and veterinary medicines. Pharmaceutical residues in treated drinking water, fish filets and crops have been documented in the scientific literature and received attention in the popular press, but the majority of environmentally realistic exposure levels are markedly lower than human therapeutic doses, indicating limited human health risk in the developed world. Consequently the majority of recent research efforts have focused on environmental fate, and effects and risks to aquatic and terrestrial wildlife. Whereas information on the occurrence and fate of select pharmaceuticals is increasingly reported, existing data on wildlife effects is largely available from short term (e.g., 48 hr, 7 d) standardized aquatic test results, which have been criticized for limited sensitivity because therapeutics are designed to specifically interact with biological target sites. Herein, comparative pharmacology and toxicology research can identify toxicological targets in non-target organisms and potentially develop alternative endpoints related to mode of action and methods for effects assessment. In fact, such read-across approaches from target organism pharmacology (e.g., mammals) have the potential to reduce uncertainty in environmental assessments when the presence and function of toxicological targets are understood in non-target organisms. Subsequently, this presentation will present an overview of several approaches to perform "intelligent" ecotoxicological testing of pharmaceuticals based on chemical mode of action.