Nucleotide-binding, oligomerization domain (NOD)-like receptor (NLR) proteins are a family of innate immune receptors that play a pivotal role in microbial sensing, leading to the initiation of antimicrobial immune responses. Dysregulation of the function of multiple NLR family members has been linked, both in mice and humans, to a propensity for infection and autoinflammatory disease. Despite our increased understanding of NLR function and interactions, many aspects related to mechanisms of sensing, downstream signaling, and in vivo functions remain elusive. In this review, we focus on key members of the NLR family, describing their activation by diverse microbes, downstream effector functions, and interactions with each other and with other innate sensor protein families. Also discussed is the role of microbial sensing by NLR receptors leading to activation of the adaptive immune arm that collaborates in the antimicrobial defense.