We review here a novel concept in the regulation of cardiac contractility involving variations in the activity of the multi-functional enzyme, P²¹-activated kinase1 (Pak1), a member of a family of proteins in the small G-protein signaling pathway that is activated by Cdc42 and Rac1. There is a large body of evidence from studies in non-cardiac tissue that Pak1 activity is key in regulation of a number of cellular functions including cytoskeletal dynamics, cell motility, growth, and proliferation. Although of significant potential impact, the role of Pak1 in regulation of the heart has been investigated in only a few laboratories. In this review we discuss the structure of Pak1 and its sites of post-translational modification and molecular interactions. We assemble an overview of the current data on Pak1 signaling in non-cardiac tissues relative to similar signaling pathways in the heart, and identify potential roles of Pak1 in cardiac regulation. Finally, we discuss the current state of Pak1 research in the heart in regard to regulation of contractility through functional myofilament and Ca²⁺ flux modification. An important aspect of this regulation is the modulation of kinase and phosphatase activity. We have focused on Pak1 regulation of protein phosphatase 2A (PP2A), which is abundant in cardiac muscle, thereby mediating dephosphorylation of sarcomeric proteins and sensitizing the myofilaments to Ca²⁺. We present a model for Pak1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by PP2A dephosphorylation predominates.