The α_1D-adrenergic receptor (α_1D-AR) is a G protein-coupled receptor (GPCR) that is poorly trafficked to the cell surface and largely nonfunctional when heterologously expressed by itself in a variety of cell types. We screened a library of approximately 30 other group I GPCRs in a quantitative luminometer assay for the ability to promote α_1D-AR cell surface expression. Strikingly, these screens revealed only two receptors capable of inducing robust increases in the amount of α_1D-AR at the cell surface: α_1B-AR and β₂-AR. Confocal imaging confirmed that coexpression with β₂-AR resulted in translocation of α_1D-AR from intracellular sites to the plasma membrane. Additionally, coimmunoprecipitation studies demonstrated that α_1D-AR and β₂-AR specifically interact to form heterodimers when coexpressed in HEK-293 cells. Ligand binding studies revealed an increase in total α_1D-AR binding sites upon coexpression with β₂-AR, but no apparent effect on the pharmacological properties of the receptors. In functional studies, coexpression with β₂-AR significantly enhanced the coupling of α_1D-AR to norepinephrine-stimulated Ca²⁺ mobilization. Heterodimerization of β₂-AR with α_1D-AR also conferred the ability of α_1D-AR to cointernalize upon β₂-AR agonist stimulation, revealing a novel mechanism by which these different adrenergic receptor subtypes may regulate each other's activity. These findings demonstrate that the selective association of α_1D-AR with other receptors is crucial for receptor surface expression and function and also shed light on a novel mechanism of cross talk between α₁- and β₂-ARs that is mediated through heterodimerization and cross-internalization.