Chronic pain is characterized by immense personal and socioeconomic burden and has the highest prevalence in the musculoskeletal system. There is an urgent need to gain better understanding on factors maintaining and contributing to chronic musculoskeletal pain. One proposed key factor is stress: not only elevated levels of stress, but also the functioning of stress systems and their interactions with pain processing. Yet comprehensive research is lacking. The main objective of this innovative research project is to characterize the stress systems, including their reactivity and recovery, in musculoskeletal pain while taking into account pain duration and extent. The secondary objective is to define the contribution of stress to trajectories of musculoskeletal pain, including chronification and recovery. A mixture of psychosocial, (psycho)physiological and brain measures will be used to assess the stress systems and their interaction with pain processing. A cross-sectional study will compare individuals with local versus widespread and subacute versus chronic musculoskeletal pain, and a longitudinal study will examine the temporal course in individuals with subacute localized pain. The anticipated results will provide crucial insights on the role of stress in the extent of pain symptomatology, and in conferring risk for pain chronicity, and can eventually lead to development of personalized, risk-stratified stress-targeted prevention and rehabilitation strategies.