The regulation of cytosolic calcium concentration in smooth muscle is characterized by numerous calcium permeant ion channels mediating calcium flux across the sarcolemma and sarcoplasmic reticulum, and by a substantial diversity between tissues with regard to the extent that individual channels contribute to excitation-contraction (EC) coupling. The relative complexity of calcium signaling in smooth muscle is immediately apparent if one compares the processes underlying calcium transport during EC coupling between skeletal and smooth muscle. During excitation of skeletal muscle a single neurotransmitter (acetylcholine) binds to a single type of receptor/ligand gated ion channel (nicotinic receptor), and mediates calcium flux from the sarcoplasmic reticulum to the cytosol via a single type of calcium channel-the ryanodine receptor. By contrast, smooth muscle EC coupling is marked by redundancy at every level of activation. Multiple neurotransmitters and autocoids bind to cognate receptors that include ligand-gated (ionotropic) cation channels with variable calcium permeability, and G protein coupled receptors. The former receptor/channels are analogous to the nicotinic receptor in skeletal muscle in that they generate a postsynaptic potential that alters the membrane potential, thereby regulating the activity of voltage-dependent channels, including voltage-dependent calcium channels. In addition to this function, however, one now well characterized class of ionotropic receptors are calcium permeant, and thereby directly influence EC coupling. G proteincoupled receptors also influence the behavior of calcium permeant channels in multiple ways. First, phospholipase C linked receptors result in the activation of inositol trisphosphate receptors and mediate the release of calcium from the sarcoplasmic reticulum. Second, the release of intracellular calcium by this mechanism subsequently alters the membrane potential by gating the opening of calcium-activated channels, thereby indirectly modulating the activity of voltage-dependent ion channels such as voltage-dependent calcium channels. Third, second messenger pathways are activated that result in the modulation of voltage-dependent ion channels. Finally, cation channels that are activated by second messenger pathways (metabotropic ion channels) alter membrane potential and may have substantial calcium permeability. These complex responses to extracellular signals are imposed upon a pre-existing calcium homeostasis that results from graded calcium influx through voltage-dependent calcium channels and spontaneous intracellular calcium release through ryanodine receptors. Thus the myocyte integrates numerous calcium inputs and the concentration of cytosolic free calcium ([Ca2+] i) at any given time is the net