Nicotine alters a broad spectrum of behaviors, including attention, arousal, anxiety, and memory. The cellular physiology of nicotine is comparably diverse: nicotine interacts with an array of ionotropic receptors whose gating can lead to direct depolarization of neurons or to an indirect modulation of neuronal excitability by presynaptic facilitation. Furthermore, as many laboratories have shown, the α- and β-type subunits that comprise neuronal nicotinic acetylcholine receptors (nAChRs) are encoded by multiple, homologous genes, yielding at least seven α and three β subunits, distinct in primary sequence. nAChRs that differ in subunit composition differ in pharmacology, conductance, and kinetics as well as in their permeability to and modulation by calcium. We will first discuss recent studies on the biophysics of a special (peculiar?) subset of nAChRs, focusing on heteromeric nAChRs comprised of α4β2 ± α5 or α7 ± β2 and α5. These nAChR channel subtypes are potently and differentially modulated by changes in intracellular calcium ([Ca]). Thus, the Po, τo, and desensitization kinetics of α4β2 channels are altered by changes in [Ca]int from 0 to 50 μM; nAChRs that include the α5 subunit are oppositely regulated. Mutagenesis of specific residues within the M1 to M2 domain of α4, β2, and α5 suggest a possible Ca binding "pocket." The assembly of functional nAChRs that include α5 and/or α7 and the potential role of these novel heteromeric complexes in presynaptic facilitation will also be presented.