The serotonin 5-HT(3) receptor subtype is unique among the receptors for this neurotransmitter because it has been demonstrated to be a ligand-gated ion channel capable of mediating rapid intercellular communication. This review covers the authors work performed during more than a decade in the development of 5-HT(3) receptor ligands belonging to the classes of arylpiperazines, tropanes, and quinuclidine derivatives. The discussion is focused mainly on what the authors have learned about the interaction of these structurally different ligands with their receptor and shows the way their ideas evolved along with the progress of the project. Furthermore, a summary of the most significant structure-affinity relationships, derived from the original work, is reported to support the discussion.