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First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K<jats:sub>i<\/jats:sub> equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between \u03b4\u2010opioid receptor antagonists to \u03b4\u2010agonists based solely on subtle structural changes at the C\u2010terminal region of the Dmt\u2013Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent \u03bc\u2010agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt\u2013Tic compounds were enhanced tremendously by x\u2010ray diffraction data for three potent and biologically diverse Dmt\u2013Tic opioidmimetics that led to the development of pharmacophores for both \u03b4\u2010opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between \u03b4\u2010 and \u03bc\u2010receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer\u2010associated pain is only a matter of time and perseverance. \u00a9 2003 Wiley Periodicals, Inc. 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