In recent years, the inter-relationship between the innate immune system and the central nervous system (CNS) has moved to the forefront of biomedical research, with the discovery that these two physiological systems modulate each other by a steady mutual interaction. During normal brain aging, but also under certain pathological conditions, this crosstalk can go beyond physiological control, resulting in an unresolved inflammatory response of the CNS-resident immune cells that might initiate and propagate the progression of severe tissue damage and neurodegeneration. In this review, we focus on the impact of CNS-resident cells of the innate immune system for the development of neurodegenerative diseases, review immune pathway genes that have been identified, and discuss the vicious cycle between inflammation and neurodegeneration.