Immune cell populations in the skin are predominantly comprised of dendritic cells (DCs) and macrophages. A lack of consensus regarding how to define these cell types has hampered research in this area. In this Review, we focus on recent advances that, based on ontogeny and global gene-expression profiles, have succeeded in discriminating DCs from macrophages in the skin. We discuss how these studies have enabled researchers to revisit the origin, diversity and T cell-stimulatory properties of these cells, and have led to unifying principles that extend across tissues and species. By aligning the DC and macrophage subsets that are found in mouse skin with those that are present in human skin, these studies also provide crucial information for developing intradermal vaccines and for managing inflammatory skin conditions.