Monocytes are a class of leukocytes derived from progenitors in the bone marrow and are prevalent in the blood stream. Although the main function of monocytes is to provide innate immune defenses against infection and injury, their contributions to the central nervous system (CNS) disorders are increasingly recognized. In this review article, we summarize the molecular and physiological properties of monocytes in relation to other myeloid cells. Primarily, we discuss how monocytes (or leukocytes) may affect neuronal function in diseases that are characterized by dysregulated innate immunity and cognitive dysfunction. Under these pathological conditions, monocytes and monocyte-derived cells (1) fail to remove neurotoxic products from CNS, (2) interact with astrocytes at the periphery-brain interfaces to alter synapse development and plasticity, or (3) infiltrate into the CNS to exacerbate neuroinflammation. Through these cellular mechanisms, we speculate that monocytes and other peripheral immune cells may affect brain functioning and contribute to behavioral and cognitive deficits. Better understanding of neuroimmune interactions will help the development of strategies to ameliorate neuronal and cognitive dysfunction associated with dysregulated innate immunity.