In this PhD study, the evidence for the role of central pain mechanisms in people with OA was investigated by means of a narrative and a systematic review of the existent literature. In addition, clinical criteria for recognizing central sensitization in subjects with knee OA are discussed as well as the rationale for a comprehensive integrative treatment program including pain neuroscience education and manual therapy for this population. Clinicians may find some practical problems when combining biomechanical approaches with more brain targeted approaches in a clinical setting, especially in a specific population like OA, where patients are often a bit older and tend to stick with pure biomechanical illness perceptions in line with the earlier understanding of OA. In this PhD dissertation, the rationale and tips and tricks to target the brain without ignoring the joints in patients with knee OA has been first provided in a narrative paper and afterwards tested by means of a randomized controlled trial. General conclusions achieved after this Doctoral Thesis are: -Substantial scientific evidence indicates a role for central sensitization in osteoarthritis pain including those with knee osteoarthritis, yet it is necessary to develop strategies to allow reliable and systematic recognition of patients with osteoarthritis whose pain has a (predominant) central sensitization component. -Optimum treatment for people with knee osteoarthritis pain requires a biopsychosocial approach and determination of how peripheral and central factors are contributing to pain in each patient in order to enable individualization of treatment strategies. Physical therapists are well positioned to deliver an individualized intervention because they are cognizant of the need for a biopsychosocial approach to management. -The area of pain reported by individuals with knee osteoarthritis pain is associated with some measures of central sensitization. Clinicians should be attentive for individuals with knee osteoarthritis showing extended areas of pain as this may be an indicator of altered nociceptive processing mechanisms. Pain drawings may constitute an easy and cheap way for the early identification of central sensitization in people with knee osteoarthritis pain. -Sound scientific rationale and practical guidelines have been developed for the application of a combined manual therapy and pain neuroscience education approach in patients with chronic osteoarthritis-related pain and central sensitization as their dominant pain mechanism. -In subjects with knee osteoarthritis waiting for knee joint replacement, pre-operative pain neuroscience education combined with knee joint mobilization did not produce any additional benefits over time in knee pain and disability and central sensitization measures compared with biomedical education with knee joint mobilization. Superior effects in the pain neuroscience education with knee joint mobilization group were only observed for psychosocial variables related to pain catastrophizing and kinesiophobia.In this PhD study, the evidence for the role of central pain mechanisms in people with OA was investigated by means of a narrative and a systematic review of the existent literature. In addition, clinical criteria for recognizing central sensitization in subjects with knee OA are discussed as well as the rationale for a comprehensive integrative treatment program including pain neuroscience education and manual therapy for this population. Clinicians may find some practical problems when combining biomechanical approaches with more brain targeted approaches in a clinical setting, especially in a specific population like OA, where patients are often a bit older and tend to stick with pure biomechanical illness perceptions in line with the earlier understanding of OA. In this PhD dissertation, the rationale and tips and tricks to target the brain without ignoring the joints in patients with knee OA has been first provided in a narrative paper and afterwards tested by means of a randomized controlled trial. General conclusions achieved after this Doctoral Thesis are: -Substantial scientific evidence indicates a role for central sensitization in osteoarthritis pain including those with knee osteoarthritis, yet it is necessary to develop strategies to allow reliable and systematic recognition of patients with osteoarthritis whose pain has a (predominant) central sensitization component. -Optimum treatment for people with knee osteoarthritis pain requires a biopsychosocial approach and determination of how peripheral and central factors are contributing to pain in each patient in order to enable individualization of treatment strategies. Physical therapists are well positioned to deliver an individualized intervention because they are cognizant of the need for a biopsychosocial approach to management. -The area of pain reported by individuals with knee osteoarthritis pain is associated with some measures of central sensitization. Clinicians should be attentive for individuals with knee osteoarthritis showing extended areas of pain as this may be an indicator of altered nociceptive processing mechanisms. Pain drawings may constitute an easy and cheap way for the early identification of central sensitization in people with knee osteoarthritis pain. -Sound scientific rationale and practical guidelines have been developed for the application of a combined manual therapy and pain neuroscience education approach in patients with chronic osteoarthritis-related pain and central sensitization as their dominant pain mechanism. -In subjects with knee osteoarthritis waiting for knee joint replacement, pre-operative pain neuroscience education combined with knee joint mobilization did not produce any additional benefits over time in knee pain and disability and central sensitization measures compared with biomedical education with knee joint mobilization. Superior effects in the pain neuroscience education with knee joint mobilization group were only observed for psychosocial variables related to pain catastrophizing and kinesiophobia.