The diverse effects mediated by PI3K/PTEN (phosphoinositide 3-kinase/phosphatase and tensin homologue deleted on chromosome 10) signalling in the heart clearly support an important biological and pathophysiological role for this signalling cascade. PI3Ks are a family of evolutionarily conserved lipid kinases that mediate many cellular responses to physiological and pathophysiological stimuli. Class I PI3K can be activated by either receptor tyrosine kinase/cytokine receptor activation (class I

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... ) or Gprotein-coupled receptors (class I B ), leading to the generation of phosphatidyl inositol (3,4,5)P 3 and recruitment and activation of Akt/protein kinase B, 3 0 -phosphoinositide-dependent kinase-1 (PDK1), or monomeric G-proteins, and phosphorylation of a wide range of downstream targets including glycogen synthase kinase 3b (GSK3b), mTOR (mammalian target of rapamycin), p70S6 kinase, endothelial nitric oxide synthase, and several anti-apoptotic effectors. Class I A (PI3Ka, b, and d) and class I B (PI3Kg) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3 0 -lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P 3 to generate PtdIns(4,5)P 2 . PI3Ka, PI3Kg, and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, where they modulate cell survival, hypertrophy, contractility, metabolism, and mechanotransduction. The PI3K/PTEN signalling pathways are involved in a wide variety of diseases including myocardial hypertrophy and contractility, heart failure, and preconditioning. In this review, we discuss the signalling pathways mediated by PI3K class I isoforms and PTEN and their roles in cardiac structure and function.