Opioids are well known for their highly effective analgesic properties and for their addiction-causing tendencies. The term opioid is derived from the Greek word opion, meaning “poppy juice.” Opium is obtained from the green pods of the opium poppy plant. The alkaloids morphine, codeine, and the baine are derived from opium. Animals ranging from worms to humans produce endogenous opioid peptides. The term opioid encompasses both the naturally occurring (endogenous) opioids from opium poppy and animals and semisynthetic and synthetic alkaloid drugs that interactwith opioid receptors. To date, four different opioid receptors (ORs) have been cloned: μ, δ, and κ (also known as MOR, DOR, and KOR, respectively), and nociceptin/orphanin FQ (ORL1) (1). All four receptors are expressed in the vascular endothelium, where they are uniquely positioned to transduce signals from circulating opioids (synthesized centrally or by peripheral nonneuronal cells) before they reach their target tissue, the brain. Compared to our advanced understanding of the opioid– neural axis, remarkably little is known about opioid signaling in the endothelium. Recent studies indicate that opioid–opioid receptor interactions in endothelial cells (ECs) result in increased production of nitric oxide (NO), pointing to a potential role for opioid signaling in mediating vasodilation, cell adhesion, cell survival, and angiogenesis (Figure 50.1). In this chapter, we discuss the nature and mechanisms of these interactions and explore the utility of this signaling axis as a therapeutic target in vascular diseases. HISTORY: FROM MESOPOTAMIA TO MODERN MEDICINE Opioids are inextricably linked to the history of mankind. In 3400 BC, the Sumerians of Mesopotamia called the opium poppy Hul Gil, the “joy plant” for its euphoric effect.