Dendritic cells (DCs) are antigen-presenting cells of the immune system and develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. The three major DC populations are epidermal Langerhans cells, tissue/interstitial/dermal DCs and plasmacytoid DCs. We review how gene-targeted mutations in mice have contributed to our understanding of how the various DC subpopulations develop. These studies have revealed both overlapping and distinct pathways of DC differentiation and show that there is no obvious correlation between transcription factor knockout phenotypes and a lymphoid or myeloid origin of DCs.