The stem cell kinase CD117 has recently been found to play an important role in the development of interstitial cells of Cajal (ICC), which are currently regarded as pacemaker cells of the gastrointestinal tract. CD117 is expressed in both gastrointestinal stromal tumors (GIST) and ICC, with the latter regarded by many as the progenitor cells of GIST. The authors investigated immunoreactivity of 25 normal surgically removed small intestinal tissues and correlated the findings with electron microscopy (EM) on 12 cases. In all cases CD117-positive cells were frequently seen around the myenteric plexi either singly or in groups. CD117-positive cells on immunostained sections corresponded to the cells appearing as fibroblast-like or undifferentiated primitive mesenchymal cells around the myenteric ganglia and interstitial spaces by EM. In contrast, S-100 stain revealed a fine network of positive staining throughout the muscularis. Branches of nonmyelinated axons and nerve endings were found regularly between myocytes with direct contact with muscle cells by EM. The cells that we could depict as ICC because of their distribution and staining pattern of CD117 were limited to the nonmuscular mesenchymal cells. No muscle cell-like ICC were found. Instead, the muscle cells in direct contact with nerve endings were often disfigured and the cytoarchitectural contents for muscle cells became less distinct because of lighter staining and loss of definite focal densities among actin filaments. However, these latter cells did maintain most muscle cell features, such as continuous external lamina, caveolae, and some of the peripheral densities. These findings raise a possibility that previous investigators could have included these altered muscle cells into the ICC group. It was also found that intestinal muscularis not only was richly endowed with an elaborate neural network of delicate axonal extensions and dense-core granule containing nerve endings traversing through and between myocytes, but also showed frequent synapse-like direct contact between nerve endings and muscle cells. These findings indicate that enteric nerves may play a major role in the control of intestinal motility, while CD117-positive cells play an accessory role as cells of Cajal as originally speculated. Further studies are necessary to better define and characterize interstitial cells of Cajal, which will be useful in the correlation of the vast number of data concerning the possible role of CD117-positive ICC in the pacemaker function of the intestine and oncogenesis of GIST.