The endocannabinoid system, consisting of cannabinoid1 (CB1) and cannabinoid2 (CB2) receptors, endogenous cannabinoid ligands and metabolising enzymes, is present throughout the pathways mediating responses to painful stimuli. Electrophysiological and behavioural studies have demonstrated that endocannabinoids, as well as plant-derived and synthetic cannabinoid agonists have anti-nociceptive effects in animal models of acute, inflammatory and neuropathic pain. CB1 receptors located at peripheral, spinal and supra-spinal sites are an important target mediating the antinociceptive effects of cannabinoid agonists. Recent evidence points to an additional role of CB2 receptors, particularly during inflammatory and neuropathic pain conditions. The mechanisms underlying the analgesic effects of cannabinoids are likely to involve inhibition of pre-synaptic neurotransmitter and neuropeptide release in addition to modulation of post-synaptic neuronal excitability. Modulation of pro-nociceptive and pro-inflammatory mediators from immune cells may be another mechanism by which cannabinoids exert their effects in the periphery. Points of convergence between cannabinoids and other classes of analgesic agents including the opioids and cyclooxygenase inhibitors offer further insight into the potential sites and mechanisms of interactions between these systems. The large body of pre-clinical evidence in support of cannabinoids as potential analgesic agents provides the functional framework for large-scale controlled clinical trials of the effects of cannabinoids and modulation of the endocannabinoid system during painful conditions.