Dendritic cells (DC) play pivotal roles in orchestrating immunity and tolerance, and, as such, they are key targets for immunotherapy. Exploiting their function depends on a precise understanding of the part that different DC subsets play in vivo, but attempts to identify definitive functions have been limited by problems depleting individual DC populations in mice. Inducible cell ablation via transgenic expression of a high-affinity diphtheria toxin receptor (DTR) is a new and powerful approach to DC research. Here, we discuss the impact of CD11c-DTR and Langerin-DTR mice on DC immunobiology, and we highlight the problems to be aware of when interpreting data from these models. The challenge now will be to refine transgenic strategies so that other DC subsets can be inducibly depleted in vivo.