Pain is the most common complaint of individuals with osteoarthritis but the cause of symptoms in this disorder remains unclear. Quantitative sensory testing reveals that in patients with chronic joint disease there is diffuse and persistent alteration of nociceptive (pain) pathways, irrespective of the level of activity of the underlying disease. Inflammatory mediators contribute to this plasticity either by directly activating high threshold receptors or more commonly by sensitizing nociceptive neurons to subsequent everyday stimuli. This involves early post-translational modification of receptors/ion channels and later, longer-lasting transcription-dependent mechanisms involving changes to the chemical phenotype of the neuron. Included amongst these changes are the increased production and release of various pro- and anti-inflammatory neuropeptides which have diverse actions on both circulating and resident cell populations. These neurally derived mediators act synergistically with cytokines and growth factors to contribute to ongoing tissue injury. It is becoming apparent that the interaction between a damaged joint and the sensory nervous system is far from straightforward and that activity arising from such interactions may produce not only pain but may also influence the subsequent course of the underlying disease.