Understanding interspecies sensitivity relationships is critical to ensure that the most sensitive and vulnerable species are protected from chemical exposure. To facilitate this, applications of computational approaches in aquatic toxicology are instrumental in understanding interspecific relationships of sensitivity while addressing both global rises in the number of chemicals and initiatives to reduce whole animal testing. The diversity of approaches available for interspecies extrapolation can be confounding, and where, when, and how to use and interpret the results of these approaches reliably can be a challenge. Here, we review chemometric and cheminformatic approaches available to improve interspecies extrapolations of chemical toxicity for both acute and chronic exposure scenarios. This work highlights advancements and opportunities available for ecological risk assessment. We also discuss future development of these approaches that will aid in advancing our mechanistic understanding of aquatic toxicology.