The interstitial cells of Cajal (ICC) play an important role in the control of gut motility. The recognition that the ICC cell membrane harbors the c-kit receptor (CD117) sparked rapid advancement in ICC research on the gut and certain pathologies using immunochemical and molecular methods. The question arises whether ICC exist in the upper urinary tract (UUT) and trigger motility. The present study analyzed the distribution of the c-kit receptor in the normal human UUT compared with various species. Immunohistochemistry (alkaline-phosphatase-anti-alkaline-phosphatase technique, immunofluorescence) was applied on serial sections using monoclonal and polyclonal antibodies recognizing the c-kit receptor. C-kit staining was compared with standard endothelial, epithelial, neurogenic, histiocytic, mast cell, and smooth muscle markers, as well as a negative control. Normal proximal, middle, and distal ureter segments were analyzed in rodents, carnivores, porcines, cow, and humans. In all species the c-kit receptor was detected in either round or spindle-shaped cells. Because of their antigenic profile, the round cells were identified as mast cells occurring in all layers of the ureteral wall except the urothelium and were more frequent in humans. In contrast, the population of spindle-shaped cells was marked only by anti-c-kit receptor antibodies, thus resembling ICC. These ICC-like cells were found among the inner and outer smooth muscle layers and in the lamina propria of all species. In humans, spindle-shaped cells were also found vertically oriented within the urothelium. Our morphological data present for the first time the distribution of ICC in the UUT of various species. The ubiquitous distribution in the entire pyeloureteral complex provides strong evidence that ICC generate electrical pacemaker activity within the UUT as an intrinsic system. Animal studies may help to understand the physiological importance of these ICC-like cells. The significance of these findings needs to be evaluated by functional studies and investigations of certain congenital pathologies with disturbance of the urinary outflow.