Macrophages play a critical role in HIV-1 infection and pathogenesis, acting as both target cells and regulators of innate immunity and inflammation. While CD4+ T cells were initially considered the primary targets of HIV-1, macrophages, along with conventional dendritic cells and monocytes, are now recognized as important HIV-1 target cells involved in all stages of infection, including transmission, dissemination, and viral persistence. Infected macrophages are found in various tissues, including the CNS, lymph nodes, spleen, lungs, and genitourinary tract, and can persist for long periods. They contribute to chronic inflammation and clinical disorders in HIV-1-infected individuals, even with effective antiretroviral therapy. Macrophages are heterogeneous, with tissue-resident macrophages and infiltrating macrophages derived from blood monocytes playing distinct roles. HIV-1 can infect macrophages through cell-free or cell-to-cell transmission, with cell-to-cell transfer being more efficient. The viral envelope determines the tropism of HIV-1, with M-tropic strains able to infect macrophages and CD4+ T cells. SAMHD1 is a key restriction factor limiting HIV-1 replication in macrophages, but viral auxiliary proteins like Vif, Nef, Vpu, and Vpr counteract this restriction. Other restriction factors, including SERINC, IFITM, TRIM, and APOBEC3 proteins, also inhibit HIV-1 replication. The complex interplay between macrophages and HIV-1 involves multiple stages of the viral life cycle, including entry, uncoating, reverse transcription, and integration. Understanding these mechanisms is crucial for developing strategies to target macrophages in HIV-1 pathogenesis.Macrophages play a critical role in HIV-1 infection and pathogenesis, acting as both target cells and regulators of innate immunity and inflammation. While CD4+ T cells were initially considered the primary targets of HIV-1, macrophages, along with conventional dendritic cells and monocytes, are now recognized as important HIV-1 target cells involved in all stages of infection, including transmission, dissemination, and viral persistence. Infected macrophages are found in various tissues, including the CNS, lymph nodes, spleen, lungs, and genitourinary tract, and can persist for long periods. They contribute to chronic inflammation and clinical disorders in HIV-1-infected individuals, even with effective antiretroviral therapy. Macrophages are heterogeneous, with tissue-resident macrophages and infiltrating macrophages derived from blood monocytes playing distinct roles. HIV-1 can infect macrophages through cell-free or cell-to-cell transmission, with cell-to-cell transfer being more efficient. The viral envelope determines the tropism of HIV-1, with M-tropic strains able to infect macrophages and CD4+ T cells. SAMHD1 is a key restriction factor limiting HIV-1 replication in macrophages, but viral auxiliary proteins like Vif, Nef, Vpu, and Vpr counteract this restriction. Other restriction factors, including SERINC, IFITM, TRIM, and APOBEC3 proteins, also inhibit HIV-1 replication. The complex interplay between macrophages and HIV-1 involves multiple stages of the viral life cycle, including entry, uncoating, reverse transcription, and integration. Understanding these mechanisms is crucial for developing strategies to target macrophages in HIV-1 pathogenesis.