There is a large body of evidence demonstrating that DCs are the most efficient and specialized APCs for T-cell priming, both in the context of host defense against pathogens and during the development of T-cell-mediated autoimmune responses; however, this concept is currently being challenged by a series of conflicting observations using genetically engineered mice in which DCs are either constitutively or inducibly ablated. In this issue of the European Journal of Immunology, Isaksson et al. [Eur. J. Immunol. 2012, 42: 2555-2563] report the use of mice in which CD11c(hi) cells can be ablated by injecting diphtheria toxin in vivo. The authors then induced EAE and found that, surprisingly, the mice were fully susceptible to the disease; thus, challenging the dogma that DCs are a mandatory APC population for the priming of autoimmune T(H) cells or T-cell-mediated immune responses. Here, we will analyze the authors' findings in the context of observations made by others and critically discuss whether DCs can really be dismissed as crucial APCs.