Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show that slow waves originate from specific sites. These pacemaker areas are populated by networks of ICC that make gap junctions with smooth muscle cells. Removal of pacemaker regions interferes with slow wave generation and propagation. (2) Chemicals that label ICC histochemically can damage ICC and abolish rhythmicity. (3) isolated ICC are spontaneously active, and several voltage-dependent ion channels, including a low-threshold Ca2+ conductance, are expressed. (4) ICC are innervated by enteric neurons, and they respond to neurotransmitters. ICC may produce nitric oxide and amplify inhibitory neurotransmission. (5) Some classes of ICC fall to develop in animals with mutations in c-kit or stem cell factor, the ligand for c-Kit receptors. Without ICC, electrical slow waves are absent. Many questions remain about the function of ICC, but modern technologies should now facilitate rapid progress toward determining the role of these cells in normal physiology and pathological conditions. (Gastroenterology 1996 Aug;111(2):492-515)