A growing body of research indicates that the stress system, and its interactions with the immune system, play a pivotal role in the aetiology and progression of rheumatoid arthritis (RA). The stress system has multiple levels and comprises physiological, psychological and environmental components. However, most investigations in RA that involve the stress system tend to focus on the interrelationships between neuroendocrine and immune function, and related disease activity, with little regard for the role of other aspects of stress system activation, including psychological variables. This is despite the fact that psychological stressors, and related psychological variables, are known to influence RA disease activity. This article aims to explore the multiple levels of stress system activation and how they may ultimately influence disease-related outcomes in RA. Some measurement issues of psychological stress will also be examined.