Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with pathologies of multiple joint tissues. Inflammation is associated with both OA pain and disease outcome and is therefore a major treatment target for OA and OA pain. Unlike TNF inhibitors and IL-1 inhibitors, established drugs such as glucocorticoids and methotrexate can reduce OA pain. Although central nociceptive pathways contribute to OA pain, crosstalk between the immune system and nociceptive neurons is central to inflammatory pain; therefore, new therapies might target this crosstalk. Newly identified drug targets, including neurotrophins and the granulocyte-macrophage colony-stimulating factor (GM-CSF)-CC-chemokine ligand 17 (CCL17) chemokine axis, offer the hope of better results but require clinical validation.