The central nervous system (CNS) is a complex network of cells involved in highly vital functions such as sensation, movement, ability to think and plan, consolidation of impulses from sense organs, awareness, and involuntary functions to name a few. Over the course of time, the concept that the brain and spinal cord were ‘immune-privileged’ has gradually changed, and it is now well-known that the CNS not only interacts with peripheral immune cells but is also capable of harbouring immune cells. This chapter covers key components of innate immunity as part of the CNS, including the blood-brain barrier and its role in maintaining homeostasis and being an interface in interaction with peripheral immune system. We also discuss about various innate immune cells including microglia, the resident macrophages that are very crucial for the CNS pathophysiology. The chapter also details mechanisms of neuroinflammation via various pattern-recognition receptors including the complement system, and the pathophysiological role the innate immunity plays in neurodegenerative diseases.