Animal models and human in vitro systems indicate that dendritic cells (DCs) have a crucial role in priming naive T cells, but just how important are they in the intact human? Recent descriptions of human DC deficiency have begun to shed light on this question and to illuminate other puzzles of human DC biology, including their haematopoietic origin, developmental regulation and homeostatic equilibrium with other leukocytes. In this Review, we explore the recently described DC deficiency syndromes, discussing what these have taught us with regard to DC function in humans and the important issues that remain unsolved.