Small bowel adenocarcinoma (SBA) is a very rare entity accounting for one-fourth of the small intestine neoplasms. Usually accompanied by nonspecific symptoms occurring late in the course of the disease, they are associated with a dismal prognosis. It appears that SBA shares several genetic characteristics with large bowel tumors, but also has unique features. The purpose of this article is to review pathogenesis and risks factors of SBA to better understand its molecular features as well as its resemblances and dissimilarities with colorectal cancer (CRC). Better understanding of sporadic and hereditary genetic pathways potentially involved will undoubtedly lead to better prevention and therapeutic management of this rare but aggressive disease.