Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases.