Like many of the papers in the Environmental Toxicology and Chemistry “Top 100” list, the development of the fathead minnow database [1] and the assignment of modes of action to the 617 chemicals therein resulted from a comprehensive research effort by a multidisciplinary team of researchers with expertise in quantitative structure–activity relationship (QSAR) modeling, chemistry, toxicokinetics, joint toxicity of chemical mixtures, and behavioral and aquatic toxicology. The fathead minnow database was the culmination of the US Environmental Protection Agency’s (USEPA) QSAR research program, which spanned nearly 20 yr, a rare program because many research planning efforts typically run within a 5-yr window of time. The vision for the USEPA QSAR program was born out of necessity. With the promulgation of the Toxic Substances Control Act in 1975, agency risk assessors needed ready access to information and new innovative methods to determine or estimate the toxicity of existing chemicals and new chemicals submitted under the premanufacturing notification program. Along with the fathead minnow database, this research effort, by USEPA scientists and collaborators, resulted in the development of methods, databases, and computational tools that are key components in risk assessments today, including the Simplified Molecular Input Line Entry System (SMILES) convention for depicting chemical structure [2] and the ECOTOX database [3].