Class I phosphoinositide 3-kinases (PI3Ks) are enzymes with both protein and lipid kinase activities that have ubiquitous cellular functions. In the heart, subclass IA PI3Ks, PI3K-α and beta, regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kgamma, the only member of subclass IB, has been shown to regulate myocardial contractility. Loss of p110γ, the catalytic subunit of PI3Kγ, enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum (SR) leading to increased cAMP-mediated phosphorylation of phospholamban. The ability of p110γ to modulate cAMP is likely mediated by the protein-protein interactions with the cAMP-degrading enzymes, phosphodiesterases, independent of its lipid kinase activity. PI3Kγ also plays a key role in modulating the cAMP response and desensitization of beta-adrenergic receptors. Loss of p110γ gamma leads to acute decompensation and rapid progression into heart failure in response to pathological biomechanical stress while lipid kinase-dead mutants were relatively resistant suggesting that elevated intracellular cAMP (and its secondary effects) is an important predisposing factor for heart failure. The commercial availability of specific PI3Kγ inhibitors may be used as therapeutic agents in inflammatory and cardiovascular diseases. In this review article, we discuss the key role of PI3Kγ gamma in regulating cAMP, Ca2+ cycling, β-adrenergic signaling and myocardial structure and function in heart disease.