A historical review of the early phases of molecular investigations of opioid receptors is presented. The ‘modern' era of molecular studies of neurotransmitter and drug receptor research commenced in the 1970s with the identification of receptors using ligand binding techniques. These findings had several ramifications. Reversible ligand binding to opioid receptors using simple, sensitive and specific techniques provided a paradigm for the study of receptors for the principal neurotransmitters in the brain. The relatively high-throughput binding techniques employed facilitated drug development in the pharmaceutical industry. Differentiation of agonist and antagonist receptor interactions by Na⁺ ions and other substances helped elucidate how ligand recognition at receptors is translated into second messenger alterations. Localizations of opioid receptors clarified many of the pharmacological actions of opiate drugs. Differential binding interactions of various drugs led to the identification of opioid receptor subtypes. Receptor influences in binding paradigms and smooth muscle pharmacology permitted the identification and isolation of endogenous opioid peptides.