The study of multiplex Crohn’s disease (CD) families has played a critical role in our understanding of the disease, including the identification of the first recognized CD risk variants in NOD2, which remain among the highest impact genetic predispositions known. Since then, genome wide association studies have revealed over 200 additional inflammatory bowel disease (IBD) risk alleles. However, such technologies may miss low prevalence, high impact variants. We therefore have been studying multiplex CD families to identify additional novel variants of disease.