for a period of days to months to years. The portfolio of compensatory mechanisms that have been described include early activation of the sympathetic nervous system and salt and water retaining systems in order to preserve cardiac output, 6–8 as well as activation of a family of vasodilatory molecules, including natriuretic peptides, prostaglandins (PGE2 and PGEI2) and nitric oxide. 9, 10 However, it bears emphasis that our understanding of the family of molecules that may be involved in this process is far from complete. Moreover, we have very little information with respect to how genetic background, gender, age, or environment impact these compensatory mechanisms. As shown in Figure 1, the compensatory mechanisms activated following the initial decline in the pumping capacity of the heart are able to modulate LV function within a physiological/homeostatic range, such that the functional capacity of the patient is preserved or is depressed only minimally. Thus, patients may remain asymptomatic or minimally symptomatic for a period of years. However, at some point in time patients will become overtly symptomatic, with a resultant striking increase in morbidity and mortality. Why this transition to symptomatic heart failure occurs, and exactly how this transition occurs, and whether it occurs in all patients with LV dysfunction remains unknown and represents an important area of discovery in heart failure. What is known, however, is that the transition to symptomatic heart failure is accompanied by further activation of neurohormonal and cytokine systems, as well as a series of adaptive changes within the myocardium, collectively referred to as LV remodeling. Although there are further modest declines in the overall pumping capacity of the heart during the transition to symptomatic heart failure, the weight of experimental and clinical evidence suggests that heart failure progressions occur independently of the hemodynamic status of the patient. Accordingly, it becomes difficult to ascribe the transition to symptomatic heart failure to worsening LV function alone. Thus, one important question that arises from the above discussion is why heart failure progresses.