Innate immune receptors such as the nucleotide-binding domain, leucine-rich repeat-containing (NBD-LRR) receptors, referred to as NLRs, are known to serve as a critical component of host defense. However, their participation in inflammatory responses within immune privileged sites such as the brain and eye is less understood. The potential importance of NLRs in regulation of inflammation within these particular sites is further underscored by their association with autoinflammatory disorders, wherein localized inflammation can occur within the brain or eye as neuroinflammation or uveitis, respectively. Many NLRs are expressed within the brain and eye and in this review, we discuss their roles in the inflammation of the central nervous system (CNS) and uveitis.