Innate immunity, with macrophages playing a central role, is critically important in the pathogenesis of RA. Although environmental insults such as smoking have been implicated in the initiation of rheumatoid arthritis (RA) in patients who express the shared epitope, the understanding of the role of innate immunity in the pathogenesis of this disease is also expanding. As the understanding continues to expand, enticing targets for new therapeutic interventions continue to be identified. This article focuses on cells of myelomonocytic origin, their receptors, and factors that interact with them.