Ca_V1/Ca_V2 channels, comprised of pore-forming α₁ and auxiliary (β,α₂δ) subunits, control diverse biological responses in excitable cells. Molecules blocking Ca_V1/Ca_V2 channel currents (I_Ca) profoundly regulate physiology and have many therapeutic applications. Rad/Rem/Rem2/Gem GTPases (RGKs) strongly inhibit Ca_V1/Ca_V2 channels. Understanding how RGKs block I_Ca is critical for insights into their physiological function, and may provide design principles for developing novel Ca_V1/Ca_V2 channel inhibitors. The RGK binding sites within Ca_V1/Ca_V2 channel complexes responsible for I_Ca inhibition are ambiguous, and it is unclear whether there are mechanistic differences among distinct RGKs. All RGKs bind β subunits, but it is unknown if and how this interaction contributes to I_Ca inhibition. We investigated the role of RGK/β interaction in Rem inhibition of recombinant Ca_V1.2 channels, using a mutated β (β_2aTM) selectively lacking RGK binding. Rem blocked β_2aTM-reconstituted channels (74% inhibition) less potently than channels containing wild-type β_2a (96% inhibition), suggesting the prevalence of both β-binding-dependent and independent modes of inhibition. Two mechanistic signatures of Rem inhibition of Ca_V1.2 channels (decreased channel surface density and open probability), but not a third (reduced maximal gating charge), depended on Rem binding to β. We identified a novel Rem binding site in Ca_V1.2 α_1C N-terminus that mediated β-binding-independent inhibition. The Ca_V2.2 α_1B subunit lacks the Rem binding site in the N-terminus and displays a solely β-binding-dependent form of channel inhibition. Finally, we discovered an unexpected functional dichotomy amongst distinct RGKs— while Rem and Rad use both β-binding-dependent and independent mechanisms, Gem and Rem2 use only a β-binding-dependent method to inhibit Ca_V1.2 channels. The results provide new mechanistic perspectives, and reveal unexpected variations in determinants, underlying inhibition of Ca_V1.2/Ca_V2.2 channels by distinct RGK GTPases.