Various concepts have served as the basis for the development of models to explore the relationship between molecular structure and biological activity. In this presentation I have outlined five concepts that have been useful in our investigation of opioid receptor multiplicity and in the design of selective opioid receptor antagonists. The first of these, the multiple binding modality concept, led to our application of four other concepts in the development of opioid receptor probes. Some of these probes are now standard tools in opioid research. These include the mu-selective affinity label beta-FNA (10), the kappa opioid receptor antagonist norBNI (15), and the delta opioid antagonist NTI (20). These highly selective antagonists have advantages over the universal opioid antagonists naloxone and naltrexone because they are of value in probing the interaction of endogenous opioid peptides with opioid receptor types. Additionally, they are useful in evaluating the selectivity of new opioid agonists. Also, selective opioid antagonists have potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include constipation, immune function, drug addiction, and alcoholism, to name only a few.