Rho GTPases regulate diverse cellular processes ranging from cell morphology and motility to mitosis. The activation of Rho GTPases is tightly controlled by the actions of guanine nucleotide exchange factors (GEFs). While the mechanism of canonical Dbl family exchange factors is established, both DOCK proteins and SmgGDS catalyze nucleotide exchange by distinct mechanisms. The structure of the DOCK9 GEF domain bound to Cdc42 was recently described, while no structural information on SmgGDS is available. Here, we describe a C-terminal DOCK9 fragment, soluble in bacteria, that is sufficient to catalyze nucleotide exchange on Cdc42. We also provide evidence that full-length DOCK9 is significantly more active than the minimal GEF domain, implicating the ability of other domains to contribute to the DOCK9 exchange mechanism. In contrast to the reported ability of SmgGDS to activate both Rho and Ras family GTPases, we find exclusive activation of RhoA and RhoC both in vitro and in vivo. The mechanism of SmgGDS nucleotide exchange is shown to be distinct from Dbl family GEFs and to require the presence of an intact C-terminal polybasic region on the GTPase. Using a homology model of SmgGDS, an electronegative surface patch and a highly conserved binding groove are identified that are required for the ability of SmgGDS to interact with RhoA. Our results illustrate that further structural characterization is necessary for a fuller understanding of DOCK9 exchange and that SmgGDS is able to function as a bona fide GEF solely for RhoA and RhoC and does so through a unique interface distinct from other known Rho family exchange factors.