The muscular coat of the gastrointestinal (GI) tract has the task of providing proper motor activity for moving nutrients and wastes, but its relative isolation from the contents of the gut lumen make it necessary for communications to be relayed from the luminal epithelium to the smooth muscle cells of the tunica muscularis. Mucosa-to-motility communication is the job of the intrinsic nerves of the gut, the enteric nervous system, and to circulating hormones. Enteroendocrine cells, of which there are at least 14 varieties, populate the luminal mucosae of the GI tract and provide the first level of sensory input. These cells transduce information about the luminal contents into both neural and hormonal signals. The largest subgroup of enteroendocrine cells is the enterochromaffin (EC) cells that are mechanosensitive and chemosensitive and sense luminal contents and composition. When stimulated, EC cells release 5-HT into the interstitium of the lamina propria in close proximity to mucosal processes of intrinsic primary afferent neurons (IPANs). 5-HT3 receptors expressed by IPANs bind 5-HT and activate action potentials that convey sensory information into the enteric nervous system. IPANs are Dogiel type II (AH) neurons with multiple processes and cell bodies in the ganglia of the myenteric plexus and submucous plexus. Information flow through the mucosal projection of a given AH neuron is routed to the myenteric or submucosal ganglion housing the cell body and distributed via its multiple processes to other AH neurons, interneurons and motor neurons to the muscle or via secretomotor neurons to the mucosa. Processing and dispersion of sensory information via IPANs and interneurons lead to activation of motor neurons to initiate motor patterns and secretion appropriate for processing and movement of the luminal contents. Sensing of nutrients and/or distension, for example, tends to induce a peristaltic reflex, described classically as a propulsive contraction developing just proximal to the site of stimulation and receptive relaxation of the segment immediately below the site of stimulation. This motor pattern can develop into a ring of propagating contraction that moves luminal contents in the aboral direction along the alimentary canal. Forces are generated by excitation of the smooth muscle cells (SMCs) lining the GI organs. SMCs are arranged in most areas of the gut into an outer layer of cells running in the longitudinal direction of the organ and an inner layer arranged in a circumferential manner. The thicker circular muscle layer provides the main force in propulsive contractions. Both inhibitory and excitatory motor neurons innervate the smooth muscle layers and release a variety of neurotransmitters. Post-junctional cells with receptors for motor neurotransmitters and effector systems able to modulate the excitability of the muscles include SMCs, interstitial cells of Cajal (ICC) and PDGFRα+ cells. Coordination of motor inputs by enteric ganglia and appropriate responsiveness of post-junctional cells produce net contraction or relaxation of segments of GI organs that constitute the stereotypical motor patterns of GI motility. This lecture will describe the details of the complex regulatory pathways of mucosa-to-motility communication and concentration will be given to emerging concepts and new methods of studying the cellular elements and integration of this system.