It is becoming increasingly evident that the sex of an organism is a critical determinant of responsiveness to opioid analgesics. However, the factors that determine the magnitude and direction of sex differences in opioid antinociception have not been fully elucidated. One factor that has received attention is the relative efficacy of the opioid. This review summarizes recent findings in which opioid efficacy was systematically manipulated as an independent variable to probe underlying sex differences in opioid system function. Overall, in rodents and nonhuman primates, mu and kappa opioids are generally more potent and effective in males than in females. The data indicate that although sex differences in the potency of high efficacy opioids such as morphine are generally less than 3.0-fold, sex differences with lower efficacy opioids can be greater than 90-fold. Moreover, that these drugs can function as full agonists in males while functioning as antagonists in females under identical conditions suggests some fundamental sex difference in opioid system function. In addition to efficacy, a number of other variables can affect the outcomes of these studies, including the drug history, genotype, and nociceptive stimulus modality, duration, and intensity. These factors may interact with opioid efficacy to determine the specific conditions under which sex differences are observed. The testing of low efficacy opioids by other laboratories and under other experimental conditions will determine the extent to which this variable affords a strategic research tool. The potential utility of low efficacy opioids in other domains of behavioral pharmacology is also discussed.