Mutation of Gαq or Gαs N-terminal contact sites for Gβγ resulted in α subunits that failed to localize at the plasma membrane or undergo palmitoylation when expressed in HEK293 cells. We now show that overexpression of specific βγ subunits can recover plasma membrane localization and palmitoylation of the βγ-binding-deficient mutants of αs or α q. Thus, the βγ-binding-defective α is completely dependent on co-expression of exogenous βγ for proper membrane localization. In this report, we examined the ability of β1-5 in combination with γ2 or γ3 to promote proper localization and palmitoylation of mutant αs or αq. Immunofluorescence localization, cellular fractionation, and palmitate labeling revealed distinct subtype-specific differences in βγ interactions with α subunits. These studies demonstrate that 1) α and βγ reciprocally promote the plasma membrane targeting of the other subunit; 2) β5, when coexpressed with γ2 or γ3, fails to localize to the plasma membrane or promote plasma membrane localization of mutant αs or αq; 3) β3 is deficient in promoting plasma membrane localization of mutant αs and αq, whereas β4 is deficient in promoting plasma membrane localization of mutant αq; 4) both palmitoylation and interactions with βγ are required for plasma membrane localization of α.