Here we report that neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and their corresponding high-affinity receptors (TrkC and TrkB) are widely expressed in cycling hair follicles (HF) in C57BL/6 murine back skin. During stages 1-3 of embryonic+ neonatal murine pelage HF development BDNF-, NT-4-, TrkB-, and TrkC-immunoreactivity (IR) was seen in hair plug keratinocytes (KC), while NT-3-IR was observed only in dermal fibroblasts. During developmental stages 4-5, BDNF-IR was found mostly in the outer root sheath (ORS), TrkB-IR in dermal papilla (DP) fibroblasts, and TrkC-IR in developing sebocytes as well as in hair bulb KC. Fully developed HF (stage 8) were characterized by the expression of TrkC-IR in sebocytes, NT-3-, TrkC-, BDNF-, and TrkB-IR in ORS, NT-3, TrkC-, and TrkB-IR in hair bulb KC, and NT-3, TrkC-, and TrkB-IR in DP fibroblasts. The beginning of HF regression (catagen I-II) was accompanied by the appearance of NT-4- and BDNFR-IR in the ORS and hair bulb KC, and disappearance of NT-3- and TrkC-IR from DP fibroblasts, which remained TrkB-positive. Secondary germ KC displayed strong NT-3-, TrkC-, and BDNF-IR, single KC of the epithelial strand showed NT-3-, NT-4-, and TrkB-IR, while no IR was found in DP during catagen VI-VII. Investigating the early steps of HF morphogenesis in NT-3 overexpressing transgenic mice (J Cell Biol 134: 487), we observed a significant increase in the percentage of HF in stages 5-6 (p<0.05), compared to control animals. Studying the first catagen in BDNF-knockout (-/-) mice, we found a retardation of HF regression, compared to heterozygote (+/-) and wild type (+/+) animals. The extensive, but spatiotemporally restricted expression patterns of NT-3, BDNF, NT-4, and their high affinity receptors in the key regions of developing and regressing murine HF, and the changes in HF development and cycling, observed in neurotrophin mutants, suggest that neurotrophins play a previously unexpected role in murine hair follicle morphogenesis and regression.