Purpose of review Immune reactions to drugs can cause a variety of diseases involving organs such as the skin, liver, kidney, and lung. Although the role of T cells in hypersensitivity reactions to drugs (HDRs) have been demonstrated by several studies, little is known about the role of the innate immune system, served mainly by dendritic cells, in the hypersensitivity response. Recent findings Our knowledge about the mechanisms of HDRs is very superficial, and the hypotheses for the involvement of reactive metabolites in many cases are circumstantial and with no evidence. It is not clear which group of HDRs is due to reactive metabolites, nor is it clear the mechanisms by which reactive metabolites can cause allergic reactions. Several studies support the hypothesis that drugs interact differently with dendritic cells from drug-allergic and nonallergic patients, modifying their maturation level. Dendritic cells are also able to metabolize drugs and to present their metabolites to T lymphocytes eliciting a hypersensitivity response. All these findings show that the innate immune system and mainly dendritic cells might play a critical role in drug allergy. Summary The interaction of drugs with dendritic cells is an emerging area of research which can bring new insights in order to have a better understanding about the physiopathology of HDRs.