Human aromatase is a cytochrome P450 (CYP19) enzyme that catalyzes the biosynthesis of all estrogens from androgens. Suppressing estrogen through aromatase inhibition allows for the treatment of hormone-sensitive breast cancer. Several classes of inhibitors for aromatase have been developed, but important side effects from prolonged clinical use call for new, more potent, and less toxic CYP19 inhibitors. Through a combination of structure-based and ligand-based pharmacophore modeling approaches, coupled with database screening and biological assessment, four new small molecule aromatase inhibitory chemotypes - distinct from the two aromatase inhibitors currently in clinical use - have been identified, with IC₅₀s ranging from 1.25 to 50.5 µM. Interestingly, these compounds affect early development in zebrafish, an observation that agrees with previous published analyses of the phenotypic effects of aromatase inhibition during zebrafish development. The integrated systems biology strategy presented in this study demonstrates that it can be effectively used to identify the next generation of aromatase inhibitors that are highly specific with fewer adverse side effects for breast cancer treatment.