The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric guanine nucleotide–binding protein (G protein) Gα_q and thereby links Gα_q-coupled receptors (GPCRs) to the activation of the small-molecular-weight G protein RhoA. We determined the crystal structure of the Gα_q-p63RhoGEF-RhoA complex, detailing the interactions of Gα_q with the Dbl and pleckstrin homology (DH and PH) domains of p63RhoGEF. These interactions involve the effector-binding site and the C-terminal region of Gα_q and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Gα_q effectors that appear to activate RhoA both in vitro and in intact cells. We propose that this structure represents the crux of an ancient signal transduction pathway that is expected to be important in an array of physiological processes.