The host has developed an array of systems that enables protection against infection and response to injury, ultimately resulting in the generation of a pro-inflammatory response. The most rapid immune response is mediated via the innate immune system, which is comprised of germ line encoded pathogen recognition receptors (PRRs). This PRR mediated system functions by specifically recognizing conserved structures of microbial molecules or products, known as microbial-associated molecular patterns (MAMPs), ultimately enabling transduction of signaling cascades, gene transcription and the development of a pro-inflammatory innate immune response. The intracellular PRRs nucleotide-binding oligomerization domain protein 1 (NOD1) and NOD2 will be the focus of this review. A brief overview of NOD1 and NOD2 and recent advances in the field regarding the intracellular location and mechanisms of NOD1 signaling will be discussed. These new findings have broadened our understanding of the mechanisms whereby NOD1 signaling results in the induction of the cellular degradation pathway of autophagy and the development of pro-inflammatory responses that activate the adaptive immune system.