Dendritic cells (DCs) are antigen sampling sentinels of the peripheral tissue and specialists for antigen capture, processing, and presentation to T cells as well as T-cell priming. By virtue of their mission as antigen samplers, they populate the body surfaces that line the border of our organism with the environment such as the skin and the mucosa of the respiratory and the gastrointestinal tract. Although all DCs share some classic features, their individual organ-specific phenotype and function are ascertained by a complex, dynamic network of coregulatory factors provided by their microenvironment. DC subtypes might initiate novel inflammatory immune responses as well as accelerate or break down ongoing inflammatory immune reactions in the skin, the gut, and the respiratory tract. On the basis of the recognition of self-signals or nonself-signals in the presence or absence of danger signals, the interplay of DC antigen uptake and presentation leads into immunosilencing or immunoactivating properties, which designate the outcome of tolerance or defensive immunity within the skin, the gut, or the respiratory tree.