Although an increasingly large amount of data exists on the acute and chronic aquatic toxicity of pharmaceuticals, numerous questions still remain. There remains a dearth of information pertaining to the chronic toxicity of bivalves, benthic invertebrates, fish, and endangered species, as well as study designs that examine mechanism-of-action (MOA)-based toxicity, in vitro and computational toxicity, and pharmaceutical mixtures. Studies examining acute toxicity are prolific in the published literature; therefore, we address many of the shortcomings in the literature by proposing "intelligent" well-designed aquatic toxicology studies that consider comparative pharmacokinetics and pharmacodynamics. For example, few studies on the chronic responses of aquatic species to residues of pharmaceuticals have been performed, and very few on variables that are plausibly linked to any therapeutic MOA. Unfortunately, even less is understood about the metabolism of pharmaceuticals in aquatic organisms. Therefore, it is clear that toxicity testing at each tier of an ecological risk assessment scheme would be strengthened for some pharmaceuticals by selecting model organisms and endpoints to address ecologically problematic MOAs. We specifically recommend that future studies employ AOP approaches (Ankley et al. 2010) that leverage mammalian pharmacology information, including data on side effects and contraindications. Use of conceptual AOP models for pharmaceuticals can enhance future studies in ways that assist in the development of more definitive ecological risk assessments, identify chemical classes of concern, and help protect ecosystems that are affected by WWTP effluent discharge.