During the past decade, scientific research has provided new insight into the development from an acute, localised musculoskeletal disorder towards chronic widespread pain/fibromyalgia (FM). Chronic widespread pain/FM is characterised by sensitisation of central pain pathways. An in-depth review of basic and clinical research was performed to design a theoretical framework for manual therapy in these patients. It is explained that manual therapy might be able to influence the process of chronicity in three different ways. (I) In order to prevent chronicity in (sub)acute musculoskeletal disorders, it seems crucial to limit the time course of afferent stimulation of peripheral nociceptors. (II) In the case of chronic widespread pain and established sensitisation of central pain pathways, relatively minor injuries/trauma at any locations are likely to sustain the process of central sensitisation and should be treated appropriately with manual therapy accounting for the decreased sensory threshold. Inappropriate pain beliefs should be addressed and exercise interventions should account for the process of central sensitisation. (III) However, manual therapists ignoring the processes involved in the development and maintenance of chronic widespread pain/FM may cause more harm then benefit to the patient by triggering or sustaining central sensitisation.