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In an attempt to explain how and why some individuals with musculoskeletal pain develop a chronic pain syndrome, Lethem et al. (Lethem J, Slade PD, Troup JDG, Bentley G. Outline of fear-avoidance model of exaggerated pain perceptions. Behav Res Ther 1983; 21: 401-408).Introduced a so-called 'fear-avoidance' model. The central concept of their model is fear of pain. 'Confrontation' and 'avoidance' are postulated as the two extreme responses to this fear, of which the former leads to the reduction of fear over time. The latter, however, leads to the maintenance or exacerbation of fear, possibly generating a phobic state. In the last decade, an increasing number of investigations have corroborated and refined the fear-avoidance model. The aim of this paper is to review the existing evidence for the mediating role of pain-related fear, and its immediate and long-term consequences in the initiation and maintenance of chronic pain disability. We first highlight possible precursors of pain-related fear including the role negative appraisal of internal and external stimuli, negative affectivity and anxiety sensitivity may play. Subsequently, a number of fear-related processes will be discussed including escape and avoidance behaviors resulting in poor behavioral performance, hypervigilance to internal and external illness information, muscular reactivity, and physical disuse in terms of deconditioning and guarded movement. We also review the available assessment methods for the quantification of pain-related fear and avoidance. Finally, we discuss the implications of the recent findings for the prevention and treatment of chronic musculoskeletal pain. Although there are still a number of unresolved issues which merit future research attention, pain-related fear and avoidance appear to be an essential feature of the development of a chronic problem for a substantial number of patients with musculoskeletal pain.