It is a well-known phenomenon that diseaserelated symptoms in patients with chronic inflammatory diseases exhibit circadian rhythms. This has been studied in, e.g., patients with rheumatoid arthritis (RA) (1–7). It is the clinical experience of rheumatologists that RA patients particularly experience joint pain, morning stiffness, and functional disability in the early morning hours. It is also remarkable that these diurnal variations demonstrate large amplitudes, with the patient’s condition being poor in the early morning and disease activity being mild or moderate in the early evening. This has been demonstrated using grip strength as a parameter; grip strength was, on average, 233 mmHg at 6:00 AM and 297 mm Hg at 6:00 PM, an increase of 27.5% (3). It has been further exemplified by overall pain reported using a 0–10-point visual analog scale, with an average pain score of 6.3 at 8:00 AM and 4.5 at 6:00 PM (decrease of 28.6%) (8). Results of assessment of symptoms in large clinical trials can vary markedly depending on the time of day that the visit takes place. The causal mechanisms underlying this pronounced diurnal cycle of changes in symptoms with a maximum in the morning are relevant to the pathophysiology of RA (9,10), to clinical patient care, and to optimization of treatment strategies (11). Since circadian rhythm is generated solely in the higher brain centers of the hypothalamus, learning from these experiments of nature can provide new clues to understanding neuroendocrine–immunologic pathways relevant to rheumatic diseases. This review briefly summarizes present knowledge on how circadian rhythm is generated in the central nervous system (CNS) and addresses studies demonstrating connections between the central oscillator and neuroendocrine pathways and the periphery (peripheral inflammation). Examples of circadian rhythms of hormones, specifically in relation to RA, are discussed, as is the circadian rhythm of pain, stiffness, and functional disability in health and disease. Circadian rhythms of RA-relevant immunologic parameters, including linkage between the diurnal variation of pain (and other RA symptoms and comorbidities) and the cycle of hormonal, neuronal, and immunologic parameters, are considered. Finally, important implications regarding therapy are derived, which in the future might lead to optimized treatment of RA and other chronic inflammatory diseases. A methodologic appendix (Appendix A) explains how several studies were mathematically analyzed and their data combined.