Joint pain attributable to osteoarthritis (OA) is complex and influenced by a myriad of factors beyond local joint pathology. Current practice continues to predominantly adopt a biomedical approach to OA despite emerging evidence of the importance of a more holistic approach. This paper will summarise evidence for the presence of multidimensional pain profiles in knee joint pain and the presence of subgroups characterized by systemic features such as psychological distress, high comorbidity load or sensitisation of the nervous system. These factors have the potential to influence patient outcomes making them relevant for clinicians and highlighting the necessity of a broader multifactorial approach to assessment and treatment. This review describes the current state of the evidence for treatments of people with knee OA-related pain, including those receiving strong recommendations from current clinical guidelines, namely exercise, weight loss, self-management advice and pharmacological approaches. Other pain-modulating treatment options are emerging such as sleep and psychological interventions, pain education and multisensory retraining. The evidence and rationale for these newer therapeutic approaches is discussed. Finally, this review will highlight some of the limitations of current international guidelines for the management of OA and make recommendations for future research.