Background: Glial cell line-derived neurotrophic factor (GDNF) and a related family member, neurturin (NTN), and their cognate receptors (GFRα-1 and GFRα-2, for GDNF and NTN, respectively) are distal members of the transforming growth factor-β superfamily. They are involved in the control of murine hair follicle (HF) cycling. This study tests the hypothesis that GDNF and NTN, and their cognate receptors, are expressed in the human HF and their expression varies in the different stages of the HF cycle. Methods: The expression pattern of these proteins was examined in human HF by immunofluorescence, immunoalkalinephosphatase staining methods, and reverse transcription-polymerase chain reaction (GDNF). The functional effects (GDNF and NTN) were examined in organ culture of the microdissected HFs. Results: GDNF, NTN, GFRα-1, GFRα-2, and c-Ret proteins were weakly expressed in catagen and telogen HFs. In contrast, they were strongly expressed in the epithelial and mesenchymal compartments of the anagen HF. GDNF gene was transcribed, both in the human scalp skin and in the isolated anagen HFs (reverse transcription-polymerase chain reaction). In HF organ culture, GDNF (but not NTN) increased the number of the proliferating HF keratinocytes (Ki 67 + cells). GDNF partially protected HFs from transforming growth factor-β2-induced premature catagen transition. Limitations: None. Conclusions: GDNF, NTN, GFRα-1, GFRα-2, and c-Ret proteins are differentially expressed in the different stages of HF cycle. GFRα-mediated signaling involves c-Ret and may play a role in human HF biology. © 2008 American Academy of Dermatology, Inc.