Cardiac hypertrophy, congestive heart failure, diabetic cardiomyopathy and myocardial ischemia-reperfusion injury are associated with a disturbance in cardiac sarcolemmal membrane phospholipid homeostasis. The contribution of the different phospholipases and their related signaling mechanisms to altered function of the diseased myocardium is not completely understood. Resolution of this issue is essential for both the understanding of the pathophysiology of heart disease and for determining if components of the phospholipid signaling pathways could serve as appropriate therapeutic targets. This review provides an outline of the role of phospholipase A2, C and D and subsequent signal transduction mechanisms in different cardiac pathologies with a discussion of their potential as targets for drug development for the prevention/treatment of heart disease.