Dendritic cells (DCs), monocytes and macrophages play crucial and distinct roles in tissue homeostasis and immunity, but also contribute to a broad spectrum of pathologies and are thus attractive therapeutic targets. Potential intervention strategies aiming at manipulation of these cells will require in-depth insights of their origins and the mechanisms that govern their homeostasis. DCs and monocytes arise from common bone marrow (BM) precursor named macrophage-dendritic cell precursors (MDP), branching into exclusively DC- or monocyte-committed progenitors named common dendritic cell progenitors (CDPs) or common monocyte progenitor (cMoPs) respectively. CDPs give rise to plasmacytoid DC and migratory DC precursors termed pre-DCs. Pre-DCs seed tissues where they differentiate into the two major functionally specialized DC lineages, CD8α+/CD103+ DC1 and CD11b+ DC2. Recent evidence from our laboratory and others has showed that monocytes do not substantially contribute to all tissue macrophage populations in steady state and inflammatory conditions. Rather certain tissue macrophages in mice are derived from embryonic precursors, are seeded before birth and maintain themselves in adults by self-renewal. In addition, we now provide evidence that commitment to DC1 and DC2 subsets is imprinted early in the BM. Combining single cell sequencing with conventional transcriptomic analysis, we identified for the first time DC subset-specific precursors in the BM as well as previously unknown molecular checkpoints for DC lineage commitment as early as the CDP stage. Using again single cell sequencing and CyTOF, we also identified homologous DC progenitors in humans and redefined the human DC lineage from the BM to the tissues. These new insights into the origins of DCs, monocytes and macrophages should aid the rational design of therapies aimed at harnessing the functions of these cells in homeostasis and inflammation and will allow efficient targeting and manipulation during health and disease.