- Almost 200 years ago, Serturner isolated morphine and discovered it to be the active ingredient in opium. That was the beginning of modern era research into opiate ligands. There have been several important landmarks over the years in the opiates field, including the discovery and cloning of opioid receptors (such as μ, Δ and κ receptors), the discovery of their endogenous opioids (such as the enkephalins, endorphins and dynorphins) and understanding of the cascade of events that produce these peptides from their corresponding proteinaceous precursors. Among the various opioid agonists, selective μ-opioid agonists display the best antinociceptive activity but also the highest abuse liability, the Δ agonists have less analgesic activity and the κ agonists have strong central dysphoric effects and may only be used as peripheral analgesics. There is, therefore, a continuous effort on the part of both academia and pharmaceutical companies to develop new synthetic opiate pain relievers having better μ-receptor selectivity and fewer side effects. Two endogenous μ-receptor ligands have been discovered in recent years: endomorphins 1 and 2. They exhibit a high affinity for the μ-opioid receptor and extremely high specificity for the μ in preference to the Δ and κ receptors. In an original approach, nonpeptidic agents were developed based on the secondary structure of the enkephalins and were found to share similarities with the three-dimensional structure and receptor selectivity profile of the endomorphins. Other approaches involved modification of known morphine analogs or of endogenous ligands. This review focuses on selective μ ligands discovered or developed in the last decade. The behavioral activity and the medicinal potential of these compounds are discussed and some assessment is made as to what additional investigations still need to be undertaken.