Clinicians have long known about incomplete cross tolerance and other pharmacological differences among analgesics that act at the mu opioid peptide (MOP) receptor (previously termed MOR). How might drugs that act through the same receptor differ so markedly? One explanation could be the presence of multiple MOP receptor subtypes, as implied from animal models over the past 20 years. More recently, at least seven different MOP receptor splice variants have been isolated. Each variant selectively binds morphine and other drugs that act at the MOP receptor with high affinity. Both antisense and knockout paradigms indicate that MOP-receptor-mediated analgesia involves more than one MOP receptor splice variant. Thus, incomplete cross tolerance among MOP receptor ligands might reflect their differing selectivities for these MOP receptor subtypes.