This presentation will review basic and clinical concepts on pain and mechanisms underlying opioid analgesia. It will describe the structure, function, and cellular signaling of opioid receptors; endogenous and exogenous opioid receptor ligands; as well as central and peripheral sites of opioid actions. The presentation will also discuss novel opioid-based therapeutic strategies, developed from recently gained knowledge on opioid receptor structures and signaling, pathological pain situations, and in vivo studies, aimed at the reduction of side effects such as respiratory depression, constipation, addiction, sedation and tolerance. Lastly, clinical problems associated with opioid use will be addressed.