Byssinosis, a respiratory disease of workers on cotton, flax, and soft hemp, is classically characterized as shortness of breath, cough, and chest tightness on Mondays or the first day of return to work after a time off. Exposure to these vegetable dusts can also result in other respiratory diseases, and the term cotton dust-induced respiratory disease (CDIRD) is introduced. Although clinically characterized for more than a century, the underlying pathogenesis of CDIRD remains obscure. An allergic pathogenesis has been proposed. This article reviews previous and current research findings supporting this mechanism and raises the possibility that, in some individuals, CDIRD may be due to pre-existing or occupationally induced mold allergy.