Among several inflammatory bowel diseases, Crohn's disease is associated with inflammation that may take place in any region of the gastrointestinal tract. The inflammatory process is most commonly associated with the ileum, often spreading deep into the bowel tissues, extending into multiple forms, such as strictures and penetrations. Currently, Crohn's disease has no known cure. Various medical and surgical procedures are used to manage the condition. The underlying mechanisms of the disease are yet to be identified, with recent studies suggesting the influence of genetics, environmental factors, and the possible activity of pathogens. Newer studies also offer strong evidence that suggests a relationship between Crohn's disease and the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene, also known as inflammatory bowel disease protein 1 (IBD1) or caspase recruitment domain-containing protein 15 (CARD15). NOD2 is responsible for the mechanism in which the immune system identifies foreign microorganisms through the sensing of pathogen-associated molecular patterns in microorganisms. NOD2 can detect intracellular muramyl dipeptide (MDP) in the bacterial wall, thereby causing an inflammatory response. Three major mutations associated with the NOD2 gene are known to have an influence on Crohn's disease (SNP8, SNP12, and SNP13). This article will discuss a number of studies to identify whether there is a relationship between Crohn's disease and the NOD2 gene.