Abstract The opioid system comprises four receptor subtypes: μ (MOP), κ (KOP), δ (DOP) (i.e. the so-called ‘classical' opioid receptors) and the more recently identified nociceptin/orphanin FQ peptide (N/OFQ) receptor (NOP). Selective endogenous peptides, typically cleaved from larger precursor proteins, have been identified for all subtypes. Both classical and non-classical opioid receptors couple to inhibitory, pertussis toxin-sensitive G-proteins. Opioid receptors activate the same major intracellular pathways, which include: closing of voltage-sensitive calcium channels; opening of potassium channels and subsequent cellular hyperpolarization; and inhibition of cyclic AMP production through inhibition of the enzyme adenylate cyclase. All current, clinically used opioids work through activation of the MOP receptor. In an experimental setting, co-administration of MOP and DOP agonists has been shown to have a synergistic analgesic action. Administration of DOP-receptor antagonists has also been shown to reduce tolerance, physical dependence and other side effects of MOP-receptor agonists, without detriment to their analgesic action. In animal models NOP agonists are analgesic spinally and hyperalgesic supraspinally. Conversely, some NOP antagonists are analgesic at supraspinal sites. NOP knockout mice show a partial loss of tolerance to morphine and up-regulation of N/OFQ production in chronic morphine-tolerant mice. Analgesic tolerance that develops from repeated exposure to morphine was markedly attenuated in NOP knockout mice. Based on these findings an alternative route for opioid development might be the development of ligands with mixed action at MOP, DOP and NOP.