Recent identification of the first susceptibility gene for Crohn's disease has led to increasing enthusiasm for the investigation and dissection of inflammatory bowel disease. In the future, identification of additional genes and careful correlation of the genetic background with clinical features of the disease will help to elucidate the causes and cure of inflammatory bowel disease. However, caution is still needed in the short term since our present knowledge has limited influence on clinical management. This review focuses on the genetic background of inflammatory bowel disease, the process of discovering the mutations of the NOD2/CARD15 gene in Crohn's disease patients, and the functional clues of the genetic variants of this gene in relation to clinical features.