The central nervous system (CNS) tissues, including the brain, the eye, and the spinal cord, are immune‐privileged, secluded from the circulation by a complex of barriers, and equipped with their own myeloid cell population, the resident microglia. Based on the classical perspective of immune–brain interactions and on the contribution of such interactions to the progression of multiple sclerosis, an autoimmune inflammatory disease of the CNS, infiltrating macrophages were traditionally viewed as an enemy of the nervous system. However, over the past two decades, research has revealed the pivotal role of monocyte‐derived macrophages in CNS repair, and opened up a new era in understanding and treating CNS pathologies. Here, we gather current knowledge regarding macrophage broad spectrum of activities in the CNS, whose two poles correspond to the classical pro‐inflammatory M1 and the ‘alternatively‐activated’ M2 cells previously described in various non‐CNS pathologies, and their diverse, multi‐functional contribution in various neurological conditions, ranging from acute traumas to neurodegenerative disorders, and autoimmune diseases. The diverse functions are manifested by induction and resolution of inflammation as well as their involvement in neural tissue regeneration and renewal, matrix remodelling, debris clearance, and angiogenesis. A special focus is devoted to current evidence suggesting that resident microglia and infiltrating monocyte‐derived macrophages are functionally non‐redundant cell types. Taken together, these recent advances reveal a dramatic therapeutic opportunity for controlled harnessing of macrophages for repair of the damaged CNS following acute insults, in neurodegenerative conditions, and in psychiatric disorders.