Increasing evidence indicates that there is a broad and intricate repertoire of neuroimmune-related sex differences, which lead to differential physiological and pharmacological responses to neurological disorders. These dimorphic features are evident in physiological settings, including synapse remodeling and maturation, during postnatal development and have implications for a gender-specific brain wiring. Immune-competent microglia exhibit sex-specific changes in gene expression when activated, in the modulation of energy homeostasis and in neuropathological events. This new exciting line of research on microglia identifies them as critical modulators of plasticity and refinement in the CNS, and a new potential therapeutic target for neurological diseases.