E-cadherin is best known as a central molecule in adherens junctions, joining adjacent epithelial cells together, thereby safeguarding epithelial barrier function. However, recent findings have uncovered an immunological role for this adhesion molecule, linked to its expression in dendritic cells (DCs) and alternatively activated macrophages (MPHs) and its impact on intracellular signaling pathways. In this respect, E-cadherin has been shown to influence the immunogenicity/tolerogenicity of DCs through the regulation of β-catenin functionality. For Langerhans cells (LCs), the DC type found in the skin epidermis, E-cadherin is known to mediate interactions with keratinocytes (KCs), thereby immobilizing immature LCs in the epidermis and preventing their maturation. In this issue of the European Journal of Immunology, a study by Mayumi et al. [Eur. J. Immunol. 2013. 43: 270-280] now describes a role for E-cadherin in the final steps of LC differentiation from human peripheral blood monocytes. Although TGF-β induces LC-like cells, these intermediates still express the dermal DC marker DC-SIGN along with Langerin; E-cadherin ligation is sufficient to induce the full LC phenotype in these cells. Here, we place these findings in the context of current knowledge and propose new avenues for future research.