This review describes mechanisms of immune-to-brain signaling that may contribute to disease-related changes in mood, affect and behavior in chronic inflammatory rheumatic diseases. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. These immune cells relay information back to autonomic, limbic and cortical areas of the CNS to affect neural activity and consequently modify behavior, hormone release and autonomic function [1,2]. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events relating to infection and injury [3]. Equally important, homeostatic mechanisms are needed at all levels to turn off the immune response when the pathogen and injurious condition are eliminated and the repair process is completed. In individuals with chronic inflammatory diseases, such as rheumatoid arthritis (RA), there is a failure of the homeostatic regulation leading to long-term immune activation that has serious health consequences. Rheumatic disorders constitute a challenge to major psychological adaptation resources leading to higher rates of psychological disorders compared with the general population. Thus the relationship between disease pathology and psychological well being is complex.