In membranes obtained from μ-opioid receptor (MOR) expressing Chinese hamster ovary (CHO) cells (MOR-CHO), the MOR-selective agonist sufentanil produced a concentration-dependent stimulation of guanosine 5′-<i>O</i>-(3-[<sup>35</sup>S]thio)triphosphate binding to G<sub>s</sub>α that was abolished by blocking MOR with naloxone. This unequivocally demonstrates the long-debated functionality of the previously described association of MOR with G<sub>s</sub>α. Several complementary observations indicate the relevance of caveolae to MOR-coupled G<sub>s</sub>α signaling. 1) In MOR-CHO membranes, sufentanil stimulated the translocation of G<sub>s</sub>α into Triton-insoluble membrane compartments. 2) Sufentanil enhanced the coimmunoprecipitation (co-IP) of G<sub>s</sub>α and adenylyl cyclase (AC) with caveolin-1 (a marker for caveolae) from the Triton-insoluble membrane fraction of spinal cord and MOR-CHO. 3) MOR blockade (via naloxone) or G<sub>s</sub> inactivation (via cholera toxin) abolished both the increased trafficking of G<sub>s</sub>α into the Triton-insoluble membrane fraction of MOR-CHO and the augmented co-IP from spinal cord membranes of G<sub>s</sub>α and AC with caveolin-1. This indicates that these events occurred subsequent to activation of MOR and G<sub>s</sub>α. Strikingly, lesser-phosphorylated G<sub>s</sub>α, which preferentially couple to MOR (<i>Mol Brain Res</i><b>135:</b>217–224, 2005; <i>Mol Pharmacol</i><b>72:</b>753–760, 2007; <i>Mol Pharmacol</i><b>73:</b>868–879, 2008), are concentrated in caveolae, underscoring their relevance to MOR G<sub>s</sub>α signaling. MOR-stimulated trafficking of G<sub>s</sub>α and AC into caveolae and the likelihood of increased MOR G<sub>s</sub>α coupling within caveolae could suggest that they contain the downstream effectors for MOR G<sub>s</sub>α AC signaling.