HA14-1 is a small, cell-permeable nonpeptidic ligand that binds to the Bcl-2 surface pocket and blocks its biological action. HA14-1 induces apoptosis in HL-60 leukemic cells overexpressing Bcl-2 and in NIH 3T3 cells via the activation of caspases by a mechanism that is distinct from Fas-mediated apoptosis.