The pro-apoptotic Bcl-2 protein Bax initiates apoptosis in almost all apoptotic paradigms. Agents facilitating disruptive Bax insertion into mitochondrial membranes have potential as cancer therapeutics. Small molecule compounds associating with the hydrophobic groove of the pro-apoptotic Bcl-2 protein Bax have been identified and found to promote Bax-dependent, but not Bak-dependent, apoptosis. The compounds alter Bax protein stability in vitro and promote Bax insertion into mitochondria, leading to Bax-dependent mitochondrial outer membrane permeabilization and apoptosis. The compounds activating the pro-apoptotic Bcl-2 protein Bax inhibit the growth of tumors by inducing apoptosis. Pharmaceutical compositions comprising the compounds that activate Bax and induce Bax-dependent apoptosis are useful as anti-cancer therapeutic agents alone or with other anti-cancer agents. Methods for inducing apoptosis and for treating cancer involve administering the compounds to a patient in need thereof.