Crohn’s disease is the result of an abnormal immune response of the gut mucosa triggered by one or more environmental risk factors in people with predisposing gene variations, including CARD15 mutations. Epidemiological data allow assessment of familial environmental risk factors related to western lifestyle, diet, bacteria, and domestic hygiene. All findings point to refrigeration as a potential risk factor for Crohn’s disease. Furthermore, cold-chain development paralleled the outbreak of Crohn’s disease during the 20th century. The cold chain hypothesis suggests that psychrotrophic bacteria such as Yersinia spp and Listeria spp contribute to the disease. These bacteria have been identified in Crohn’s disease lesions and we discuss their pathogenic properties with respect to our knowledge of the disease. From a molecular perspective, we postulate that the disease is a result of a defect in host recognition by pathogenic bacterial components that usually escape the immune response (eg, Yop molecules), which results in an excessive host response to these bacteria.