Constitutively active μ-opioid receptors (μ* receptors) are reported to be formed following prolonged agonist treatment of cells or whole animals. μ* receptors signal in the absence of activating ligand and a blockade of μ* activation of G-proteins by naloxone and naltrexone has been suggested to underlie the profound withdrawal syndrome precipitated by these antagonists in vivo. In this issue of the Journal, Divin et al. examined whether treatment of C6 glioma cells with μ-opioid receptor agonists produced constitutively active μ-opioid receptors or other commonly reported adaptations to prolonged agonist treatment. Adenylyl cyclase superactivation was readily apparent following agonist treatment but there was no evidence of the formation of constitutively active μ-opioid receptors. This result challenges the notion that prolonged agonist exposure inevitably produces μ* receptors, and is consistent with many studies of adaptations in neurons produced by chronic agonist treatment. The investigators provide no explanation of their failure to see μ* receptors in C6 cells, but this is perhaps understandable because the molecular nature of μ* receptors remains elusive, and the precise mechanisms that lead to their formation are unknown. Without knowing exactly what μ* receptors are, how they are formed and how they signal, understanding their role in cellular adaptations to prolonged opioid treatment will remain impossible. Studies such as this should refocus attention on establishing the molecular mechanisms that underlie that phenomenon of μ* receptors.