Dendritic cells (DCs) are central in the orchestration of the various forms of immunity and tolerance. Their immunoregulatory role mainly relies on the ligation of specific receptors that initiate and modulate DC maturation resulting in the development of functionally different effector DC subsets that selectively promote T helper 1 (T_H1)-, T_H2- or regulatory T-cell responses. These DC-priming receptors include pattern recognition receptors (PRRs), which discriminate between (groups of) pathogens, as well as receptors that bind tissue factors that are produced either constitutively or in response to infection with pathogens, and characterize the type of tissue and the pathogen-specific response pattern of this tissue. Although it is becoming increasingly clear that the selective development of T-cell-polarizing DC subsets is related to the ligation of particular receptors that are involved in DC maturation, several inconsistencies with this concept remain.