Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(d-Tyr-Gly, Nle28,31)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 ≫ nonsulfated CCK-8 = L-365,260 ≥ gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(d-Tyr-Gly, Nle28,31)-CCK 26–33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.