Cigarette smoking has been causally linked to the development of multiple autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Graves' hyperthyroidism, and primary biliary cirrhosis, among others. We review the known biologic effects of cigarette smoke, in particular its actions on the immune system, and the epidemiologic evidence associating smoking with increased risk of each of these autoimmune diseases. Interactions between cigarette smoking and genetic and immunologic factors, such as the human leukocyte antigen (HLA)-shared epitope, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and anti-double stranded DNA antibodies, may point to mechanisms in disease pathogenesis.