In the past two years, knowledge about the regulation of ion conductances by opioid receptors has expanded in several directions. First, it has now been shown that all three of the major receptor subtypes act on all three of the well recognized effectors, i.e., adenylyl cyclase, calcium channels and potassium channels. Second, the opioid-mediated receptor inhibition of adenylyl cyclase has been linked to the modulation of ion channel activity /20/. Third, opioids have also been found to increase the activity of adenylyl cyclase in some preparations. Fourth, opioid receptors can mediate a rise in internal free-calcium concentration /21/. These observations suggest that the regulation of cell excitability by opioids is dependent on the cell under study and that the generalization between receptor subtype and specificity of action is no longer valid. The additional second messenger pathways affected by opioids suggest that the adaptive changes resulting from chronic opioid treatment are more complex than previously thought. This review evaluates these relatively new observations and suggests how these results may change the interpretations from previous work on opioid actions.