Langerhans cells (LCs) are bone marrow (BM)–derived epidermal dendritic cells (DCs) that develop from precursors found in the dermis. Epidermal LCs are absent in transforming growth factor (TGF) β1-deficient mice. It is not clear whether TGFβ1 acts directly on LC precursors to promote maturation or whether it acts on accessory cells, which in turn affect LC precursors. In addition, the physiologic source of TGFβ1 is uncertain because BM chimera experiments showed that neither hematopoietic nor nonhematopoietic-derived TGFβ1 is required for LC development. To address these issues, we created mice transgenic for a bacterial artificial chromosome (BAC) containing the gene for human Langerin into which Cre recombinase had been inserted by homologous recombination (Langerin-Cre). These mice express Cre selectively in LCs, and they were bred to floxed TGFβRII and TGFβ1 mice, thereby generating mice with LCs that either cannot respond to or generate TGFβ1, respectively. Langerin-Cre TGFβRII mice had substantially reduced numbers of epidermal LCs, demonstrating that TGFβ1 acts directly on LCs in vivo. Interestingly, Langerin-Cre TGFβ1 mice also had very few LCs both in the steady state and after BM transplantation. Thus, TGFβ1 derived from LCs acts directly on LCs through an autocrine/paracrine loop, and it is required for LC development and/or survival.