Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that are used to address the issue of gene-environment interactions in the etiology of RA, and discuss relevant examples of such interactions. We focus on how smoking, the best-known environmental risk factor for RA, interacts with HLA-DR shared epitope genes, the main genetic risk factors for RA, and result in a high risk of RA in individuals exposed to both of these risk factors. From these and other related findings, we can begin to define the distinct environmental risk factors (such as smoking) that in certain genetic contexts (for example, the presence of HLA-DR shared epitope alleles) can trigger immune reactions (such as autoantibodies to citrullinated peptides) many years before onset of RA, and consider how these immune reactions might contribute to clinical symptoms in a subset of affected patients. Increased knowledge about these and other events involved in the development of RA should enable the design of new tools for suppressing RA pathogenesis before the onset of disease.