Multiple proven and potential risk factors for the development of rheumatoid arthritis (RA) have been identified, and represent interactions between genes and the environment. Proven risk factors include genetic influences on the function of the innate and adaptive immune systems, smoking, anti-citrullinated protein antibodies (ACPAs), and rheumatoid factors (RF). Potential risk factors include epigenetic control of gene expression, the microbiome and other environmental factors, Toll-like receptors, cytokines, and Fc receptors. Preclinical abnormalities such as circulating RF and ACPAs may occur more than 10 years prior to the onset of clinical disease. However, the precise mechanisms whereby these risk factors lead to clinical disease remain unclear. It is possible that, combined with activation of the innate immune system, a subset of ACPAs initiates the disease in the cartilage or synovium after binding to endogenous citrullinated proteins. Subsequent engagement of Fc receptors and complement activation would lead to secondary inflammation in the synovium with induction of a perpetuating cycle of chronic synovitis.