Crohn’s disease (CD) is an inflammatory bowel disease of unknown etiology. During the last decades, significant technological advances led to development of -omic datasets allowing a detailed description of the disease. Unfortunately, these have not, to date, resolved the question of the etiology of CD. Thus, it may be necessary to (re)consider hypothesis-driven approaches to resolve the etiology of CD. According to the cold chain hypothesis, the development of industrial and domestic refrigeration has led to frequent exposure of human populations to bacteria capable of growing in the cold. These bacteria, at low levels of exposure, particularly those of the genus Yersinia, are believed to be capable of inducing exacerbated inflammation of the intestine in genetically predisposed subjects. We discuss the consistency of this working hypothesis in light of recent data from epidemiological, clinical, pathological, microbiological and molecular studies.