Heart failure, a major symptom in the progression of cardiac hypertrophy, is a critical risk factor for cardiac death. A large body of research has investigated cardioprotective mechanisms that prevent or minimize hypertrophy, identifying a variety of specific peptide hormones, growth factors, and cytokines with cardioprotective properties. Recent investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR). Using genetically modified transgenic or knockout mice and adenoviral targeting to manipulate expression or function in experimental models of heart failure, several investigators have demonstrated that the PI3K-Akt pathway regulates cardiomyocyte size, survival, angiogenesis, and inflammation in both physiological and pathological cardiac hypertrophy. In this review, we discuss the reciprocal regulation of PI3K, Akt and mTOR in cardiomyocytes and their association with cardiac disease.