The nicotinic acetylcholine receptor is the prototype of the ionotropic receptor superfamily of proteins, which includes the closely related gamma- aminobutyric acid type A and glycine receptors, and more distantly related serotonin type-3 and glutamate receptors. Several models of the transmembrane topology of the nicotinic acetylcholine receptor subunits were originally proposed based on hydropathy analysis of their deduced amino acid sequences. Antibodies specific to different epitopes of the nicotinic acetylcholine receptor have proven to be valuable probes for examining the validity of those models. Despite important caveats, a viable model for the transmembrane structure and functional topology of the nicotinic acetylcholine receptor subunits has been obtained from the antibody mapping studies. This model, and the associated methodological shortcomings and obstacles that were overcome in the process of its formulation, can legitimately be extended to other members of the ionotropic receptor superfamily and to other membrane proteins as well.