Nucleotide-binding oligomerization domain-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) and able to respond to conserved microbe-associated molecular patterns (MAMPs) and endogenous damage-associated molecular patterns (DAMPs). NLRs modulate the inflammatory response via multiple pathways including nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB)-activation, mitogen-activated protein kinase (MAPK)-pathways and both canonical and non-canonical inflammasome formation. The latter results in auto-processing of caspase-1 and subsequent maturation of the cytokines interleukin 1 beta (IL-1β) and IL-18 as well as induction of pyroptosis by cleavage of gasdermin D (GSDMD) that induces pores in the cell membrane. NLRs act in synergy with other PRRs but some NLRs directly modulate adaptive immunity via transcriptional regulation of major histocompatibility complex (MHC) class I and class II. NLRs have an essential role as intracellular PRRs and thereby orchestrate inflammatory responses. NLR mutations and subsequent dysfunction can result in cancer or autoinflammatory diseases, such as Crohn’s disease and ulcerative colitis, and many more, indicating their important role in classical immune recognition, maintenance of tissue homeostasis and reproductive functions. Here, we discuss our current understanding of mammalian NLRs that act as PRRs.