Over the last 10 years, sensitive advancement has been made in the study of genetic susceptibility to inflammatory bowel disease (IBD). Complementary methodologies of linkage, fine-mapping and candidate-gene studies have led to the identification of a number of susceptibility genes and loci, including caspase activation and recruitment domain 15 (CARD15), major histocompatibility complex (MHC) and IBD5, whereas many other genes (nucleotide oligomerization domain 1 [NOD1], tumor-upregulated CARD-containing antagonist of caspase-9 [TUCAN], Toll-like receptors [TLR], interleukin 23 receptor [IL23R], multidrug resistance 1 [MDR1], myosin IXb [MYO9B], chemokine [C-Cmotif] ligand 20 [CCL20], human beta-defensin 2 [HBD-2], autophagy-related 16-like 1 [ATG16L1]) are still awaiting confirmation. The CARD15 gene is currently the most widely replicated and investigated gene. The exact sequence of events that link CARD15 variants to early pathogenetic changes is unknown. However, the role of the encoded protein confirms the relevance of appropriate responses by the innate immune system to intestinal bacteria, including the production of antimicrobial peptides (defensins). With the implementation of new genomics and proteomics methodologies, genetic research will advance our further understanding of the clinical heterogeneity of IBD and tackle the complex interactions between genetic and environmental risk factors.