Phosphoinositide 3-kinases (PI3Ks) are important signaling proteins in the heart. Class I_A PI3Ks (p110α, β) are critical regulators of physiological heart growth and cell survival, and are generally considered to be beneficial for heart function. In contrast, activation of class IB PI3K(p110γ) is detrimental for heart function, reducing cardiac contractility. This may have implications for the treatment of heart disease and failure. In vitro, ex vivo and in vivo studies have contributed to our understanding of PI3K signaling in the heart. This review summarizes class I PI3K signaling in the regulation of cardiac function, with a particular focus on the role of different PI3K isoforms in settings of heart disease.