Rheumatoid arthritis (RA) is a chronic inflammatory illness that primarily affects the joints. It is associated with symptoms of fatigue, pain, and sleep disturbances that can overlap with or mimic symptoms of depression. Depressive symptoms are highly comorbid with RA and may occur with at least mild severity in up to 42% of RA patients. RA and depression contribute to mortality, decreased quality of life, increased health care costs, and disability. Inflammatory pathways may hold the key to a link between depression and RA, and cytokines have been a major target of research in this area. This article reviews some of the most recent research and commentary on this complex relationship.