See related article this issue, pages 855–864. model, Shh interacts with and blocks the function of a cell-surface receptor called Ptch1, which normally inhibits a third protein called Smo (15). During embryogenesis, Shh-mediated derepression of Smo results in temporally and spatially restricted activation of Shh target genes, which include the transcription factor Gli1 and Ptch1 itself. The expression level of these transcripts is thus a reliable indicator of Shh pathway activity. Intense interest in Shh signaling in skin was fueled by the discovery that loss-of-function mutations affecting the PTCH1gene occur in both familial and sporadic basal cell carcinoma (16, 17), resulting in constitutive Shh pathway activation. What is the normal function of Shh in skin? During development, Shh expression is restricted to the epithelial placode of primordial hair follicles, whereas Ptch1 mRNA is detected in both the placode and dermal condensate (Figure 1)(18, 19). This expression pattern suggested a role for Shh signaling in developing skin, and analysis of Shh mutant mice revealed that this molecule was required for hair follicle morphogenesis (20, 21). Although placodes and dermal condensates were detected in both wild-type and Shh–/–embryos, progression through subsequent stages of hair follicle development was severely impaired in the skin of mutant animals. These studies revealed an essential function for Shh as a fundamental growth regulator in embryonic hair follicles, and set the stage for future studies exploring the potential involvement of Shh in postnatal follicle function. In this issue, Sato et al. demonstrate that Shh, delivered by subcutaneous injection of an adenoviral expression vector, is capable of profoundly affecting the hair cycle in postnatal mice (1). They propose that Shh acts as a biologic switch that triggers telogen hair follicles to enter anagen. These investigators also demonstrate that spontaneous anagen is associated with transient upregulation of endogenous Shh and Ptch1 transcripts, suggesting that activation of the Shh pathway may be the physiological signal stimulating follicle growth. Although additional studies will be required to test this hypothesis, the data presented by Sato et al. convincingly show that transient expression of a single key regulatory molecule is sufficient to activate a complex morphogenetic program in postnatal rodent skin. Notably, the lack of any gross or histological abnormalities in skin 6 months after injection argues against any deleterious long-term consequences. What is the specific target cell responding to exogenous Shh in injected skin, and is this same cell type activated by Shh during the normal transition to anagen? Based on the nature of the technique used for their studies, it is not surprising that Shh mRNA was detected in several different cell types scattered throughout the treated areas of skin (1). What is somewhat surprising is that the induction of anagen was remarkably uniform in the injected areas despite the fact that Shh expression was mosaic. To help understand this result, it will be important to identify the cells responding directly to Shh by examining the in situ expression of Shh target genes during the normal transition to anagen and in response to exogenous Shh. Even though the expression of exogenous Shh may be widespread, responsiveness of specific cell types to Shh in the skin is likely to be tightly regulated both in space and time (22). As there is strong evidence that dermal papilla cells play a central role in regulating growth of the follicle epithelium, perhaps these are the critical target cells for Shh, and the observed