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Over the last decade, multiple studies have investigated the heterogeneity of murine conventional dendritic cells type 2 (cDC2s). However, their phenotypic similarity with monocytes and macrophages renders their clear identification challenging. By creating a protein atlas utilizing multiparameter flow cytometry, we show that ESAM+ cDC2s are a specialized feature of the spleen strongly differing in their proteome from other cDC2s. In contrast, all other tissues are populated by Clec12A+ cDC2s or Clec12A− cDC2s (high or low for Fcγ receptors, C-type lectin receptors, and CD11b, respectively), rendering Clec12A+ cDC2s classical sentinels. Further, expression analysis of CD301b, Clec12A, and FcγRIIB/III provides a conserved definition of cDC2 heterogeneity, including the discovery of putative FcγRIIB/III+ DC3s across tissues. Finally, our data reveal that cell identity (ontogeny) dictates the proteome that is further fine-tuned by the tissue environment on macrophages and dendritic cells (DCs), while monocytes and plasmacytoid DCs (pDCs) display subset intrinsic default settings. [Display omitted] • A surface protein library delineates cDC2 heterogeneity across tissues • ESAM+ cDC2s are a specialized feature of the spleen • The splenic cDC2 compartment is unrepresentative for the cross-tissue cDC2 network • Tissue cDC2 repertoires are subcategorized by Clec12A, CD301b, and FcγRIIB/III Dendritic cells are central regulators of the immune system. Amon et al. analyzed the cDC compartment across multiple murine tissues, focusing on cDC2 heterogeneity. They delineated ESAM+ cDC2s as a specialized feature of the spleen, while cDC2 heterogeneity in all tissues was multilayered and defined by Clec12A, CD301b, and FcγRIIB/III. [ABSTRACT FROM AUTHOR]