Dendritic cells (DCs) are professional antigen-presenting cells that provide a critical link between the innate and adaptive immune responses. The genetic program required for differentiation of DCs from their hematopoietic precursors is controlled by both cytokines and transcription factors. The signals transduced from cytokines recruit specific transcription factors, enabling the expression of a distinct transcriptome that is required for specification of different DC lineages. The establishment of a distinct transcriptome also depends on chromatin modifications associated with critical cis elements of lineage-specific genes. In this review, recent advances in the understanding of the transcriptional network governing DC lineage specification are summarized, along with current views of the dynamic DC epigenome.