G-protein-coupled receptors (GPCRs) have recently joined the list of cell surface receptors that dimerize. Dimerization has been shown to alter the ligand-binding, signaling, and trafficking properties of these receptors. Recent studies have shown that GPCRs heterodimerize with closely related members, resulting in the modulation of their function. In this study, we have attempted to determine whether members of GPCR superfamilies that couple to different families of G-proteins can associate and form oligomers. We chose the β₂ adrenergic receptor that couples to stimulatory G-proteins and δ & κ opioid receptors that couple to inhibitory G-proteins. β₂ and δ receptors undergo robust agonist-mediated endocytosis, whereas κ receptors do not. We find that when coexpressed, β₂ receptors can form heteromeric complexes with both δ and κ receptors. This heterooligomerization does not significantly alter the ligand binding or coupling properties of the receptors. However, it affects the trafficking properties of the receptors. For example, we find that δ receptors, when coexpressed with β₂ receptors, undergo isoproterenol-mediated endocytosis. Conversely, β₂ receptors in these cells undergo etorphine-mediated endocytosis. However, β₂ receptors, when coexpressed with κ receptors, undergo neither opioid- nor isoproterenol-mediated endocytosis. Moreover, these cells exhibit a substantial decrease in the isoproterenol-induced phosphorylation of mitogen-activated protein kinases. Taken together, these results provide direct evidence of heteromerization of GPCRs that couple to different types of G-proteins, which results in the modulation of receptor trafficking and signal transduction.