Interstitial cells of Cajal (ICC) are located in most parts of the digestive system. Although they were discovered over 100 years ago, their function began to be unravelled only recently. Morphological observations have led to a number of hypotheses on the possible physiological roles of ICC: (1) these cells may be the source of slow electrical waves recorded in gastrointestinal (GI) muscles; (2) they participate in the conduction of electrical currents, and (3) mediate neural signals between enteric nerves and muscles. These hypotheses were supported by experiments in which the ICC-containing layer was removed surgically, or when ICC were ablated chemically, and as a consequence the slow waves were absent. Electrophysiological experiments on isolated cells confirmed that ICC can generate rhythmic electrical activity and can also respond to messenger molecules known to be released from enteric nerves. In mice mutants deficient in ICC, or in mice treated with antibody against the protein c-Kit, slow wave activity was impaired. These results support the role of ICC as pacemaker cells. Physiological studies have shown that ICC in certain GI regions are important for signal transmission between nerves and smooth muscle. There is evidence that pathological changes in ICC may be associated with GI motility disorders. The full interpretation of the role of ICC in disease conditions will require much further study on the physiology and pharmacology of these cells.