Current evidence indicates that ibogaine and other iboga alkaloids might produce some of their neurotoxic effects by interaction with sigma-2 receptors. Sigma receptors are membrane proteins that bind several psychotropic drugs with high affinity. Two major subclasses of sigma receptors have been identified. These have been termed “sigma-1” and “sigma-2,” and they are differentiated by their pharmacological profile, function, and molecular size. Both subtypes have high to moderate affinity for typical neuroleptics, with haloperidol exhibiting the highest affinity for both sites. The sigma-1 receptor has been cloned in guinea pig, mouse, rat, and human, and shown to be a novel protein with > 90% species homology. Some of the functions attributed to sigma-1 receptors include the following: (1) modulation of synthesis and release of dopamine and acetylcholine, (2) modulation of NMDA-type glutamatergic receptor electrophysiology, (3) modulation of NMDA-stimulated neurotransmitter release, (4) modulation of muscarinic receptor-stimulated phosphoinositide turnover, (5) neuroprotective and antiamnesic activity, (6) modulation of opioid analgesia, and (7) alteration of cocaine-induced locomotor activity and toxicity. The ability of sigma ligands to induce morphological changes and apoptosis led to an investigation of the signaling mechanisms that are utilized by sigma-2 receptors.