Alpha and betaPIX belong to the group of guanine nucleotide exchange factors (GEFs) that mediate activation of members of the Rho GTPase family, in particular Rac1 and Cdc42, by stimulating the exchange of GDP for GTP. Rho family proteins are well known as regulators of the actin cytoskeleton and have been implicated in the formation of various types of focal adhesion structures. However, the function of GEF proteins during focal adhesion formation is only beginning to emerge. Here, we highlight the recent findings on alpha and betaPIX and their involvement in integrin-dependent signaling and suggest models for the role of PIX proteins during focal adhesion turnover.