A computational binding site similarity screen of > 14,000 ligand-binding pockets from PDB revealed an unexpected similarity between the estrogen receptor and the beta-tubulin taxane site. Evaluation of nine selective estrogen modulator receptors (SERMs) via in vivo and in vitro assays confirmed taxane site binding, microtubule modulation and cell growth inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and suggests potential drug repurposing for cancer treatment.