The development of monocytes, macrophages, and dendritic cells (DCs) is a complex process involving distinct lineage relationships and functional roles in the immune system. Monocytes circulate in the blood, bone marrow, and spleen and can differentiate into macrophages and DCs during inflammation. Macrophages are resident phagocytic cells in tissues, involved in maintaining homeostasis and responding to infection. DCs are critical for initiating adaptive immune responses and antigen presentation to T cells. Recent studies in mice have revealed new insights into the developmental pathways of these cells, though many aspects remain unclear, particularly regarding the origins and differentiation cues of tissue-specific subsets in humans. Monocytes are divided into two main subsets: Gr1⁺/Ly-6C⁺ and Gr1⁻/Ly-6C⁻. Gr1⁺/Ly-6C⁺ monocytes are involved in inflammatory responses and can differentiate into macrophages and DCs. Gr1⁻/Ly-6C⁻ monocytes are more associated with tissue repair and can differentiate into alternatively activated macrophages. DCs are further classified into classical DCs (cDCs) and plasmacytoid DCs (PDCs), with cDCs playing a key role in antigen presentation and T cell activation, while PDCs are specialized in responding to viral infections by producing type I interferons. The development of these cells is regulated by cytokines and growth factors, such as Csf1r (c-fms, M-CSFR, CD115), which is essential for the development of monocytes, macrophages, and some DCs. Transcription factors like PU.1, C/EBPα, and MafB play critical roles in determining cell fate decisions. Epigenetic modifications and microRNAs also influence lineage commitment. Despite significant progress, many aspects of monocyte and macrophage development remain unclear, particularly regarding the origins of certain tissue-specific subsets. Future research aims to clarify these relationships and understand the roles of these cells in health and disease. Advances in genetic tools and in vivo models will be crucial for further elucidating the mechanisms governing the development and function of these immune cells.The development of monocytes, macrophages, and dendritic cells (DCs) is a complex process involving distinct lineage relationships and functional roles in the immune system. Monocytes circulate in the blood, bone marrow, and spleen and can differentiate into macrophages and DCs during inflammation. Macrophages are resident phagocytic cells in tissues, involved in maintaining homeostasis and responding to infection. DCs are critical for initiating adaptive immune responses and antigen presentation to T cells. Recent studies in mice have revealed new insights into the developmental pathways of these cells, though many aspects remain unclear, particularly regarding the origins and differentiation cues of tissue-specific subsets in humans. Monocytes are divided into two main subsets: Gr1⁺/Ly-6C⁺ and Gr1⁻/Ly-6C⁻. Gr1⁺/Ly-6C⁺ monocytes are involved in inflammatory responses and can differentiate into macrophages and DCs. Gr1⁻/Ly-6C⁻ monocytes are more associated with tissue repair and can differentiate into alternatively activated macrophages. DCs are further classified into classical DCs (cDCs) and plasmacytoid DCs (PDCs), with cDCs playing a key role in antigen presentation and T cell activation, while PDCs are specialized in responding to viral infections by producing type I interferons. The development of these cells is regulated by cytokines and growth factors, such as Csf1r (c-fms, M-CSFR, CD115), which is essential for the development of monocytes, macrophages, and some DCs. Transcription factors like PU.1, C/EBPα, and MafB play critical roles in determining cell fate decisions. Epigenetic modifications and microRNAs also influence lineage commitment. Despite significant progress, many aspects of monocyte and macrophage development remain unclear, particularly regarding the origins of certain tissue-specific subsets. Future research aims to clarify these relationships and understand the roles of these cells in health and disease. Advances in genetic tools and in vivo models will be crucial for further elucidating the mechanisms governing the development and function of these immune cells.