Effective myocardial function depends primarily on oxidative energy production. In humans, at a heart rate of 60 to 70 beats per minute, the oxygen consumption normalized per gram of myocardium is 20-fold higher than that of skeletal muscle at rest. As an adaptation to this high oxygen demand, the heart maintains a high level of oxygen extraction of 70% to 80% compared with 30% to 40% in skeletal muscle. 2 This is facilitated by the capillary density of 3000 to 4000 compared with 500 to 2000 per 1 mm2 in skeletal muscle and a tight regulation of the coronary blood flow. 3 In the case of exercise-induced hypertrophy, the heart preserves the oxygen supply/demand, matching the proportional increases in cardiac myocyte size and the extent of coronary microvasculature. 3, 4 Different forms of hemodynamic stress (hypertension, aortic stenosis, coarctation of the aorta, mitral regurgitation, and myocardial infarction, among others) increase intraventricular pressure or volume and lead to a hypertrophic response. 5 A prolonged increase in wall stress may result in progressive ventricular dilation and myocardial decompensation owing to ongoing myocyte death and fibrosis and, ultimately, heart failure and death. 6, 7 This pathological progression demonstrates a mismatch between oxygen supply and demand, as the extent of cardiomyocyte hypertrophy is not matched by a corresponding increase in the arterial blood supply. 3 The human heart contains an estimated 2 to 3 billion cardiac muscle cells, but they account for fewer than a third of the total number of cells in the heart. The balance includes a broad array of additional cell types, including smooth muscle and endothelial cells of the coronary vasculature and the endocardium, fibroblasts and other connective tissue cells, mast cells, and immune system–related cells. Recently, pluripotent cardiac “stem cells” have also been identified in the heart. 8 These distinct cell pools are not isolated from one another within the heart but instead interact physically and via a variety of soluble paracrine, autocrine, and endocrine factors (summarized in Figure 1). Thus, to fully understand the biology and pathobiology of the heart, the influences of this cellular crosstalk must be considered. In this review, we discuss new insights into molecular regulation of a myocardial hypertrophic response, focusing on the contribution of cell-cell crosstalk in the heart to this process.