Previous studies have investigated the expression of insulin-like growth factor-I (IGF-I) and its receptor in cultured skin cells or in whole skin. In order to fully understand the role of IGF-I in the skin and its appendages, however, a comprehensive study that details the expression of IGF-I and the IGF-I receptor in sections of human skin is needed. Therefore, we now report an immunocytochemical and in situ hybridization localization study of the cell types expressing IGF-I and its receptor in human adult skin and its appendages. We have observed that (i) dermal fibroblasts produce IGF-I, (ii) the epidermal basal keratinocytes are IGF-I negative but IGF-I receptor positive, and (iii) the keratinocytes of the stratum granulosum produce IGF-I. These observations indicate either that the mitogenesis of the basal keratinocytes is regulated by IGF-I expressed both in the dermis and in the stratum granulosum, or that dermal fibroblasts are responsible for sequestering IGF-I to the basal keratinocytes and that the stratum granulosum-derived IGF-I may be an autocrine regulator of epidermal differentiation. The distribution of IGF-I and its receptor in the hair follicle indicates that IGF-I may be a morphogen, not a mitogen, at those sites, because their proliferating cells, but not their differentiating cells, are IGF-I receptor negative. Further, IGF-I receptor expression by the dermal papilla appears to be switched off during the transition from anagen to catagen, which implies a regulatory role for IGF-I during the hair growth cycle.