Non-uniformity exists on heart failure definitions. Heart failure includes typical signs and symptoms deriving from alterations in left ventricular systolic or diastolic function. Systolic heart failure results from the acute or chronic reduction of the left ventricular ejection fraction. Conversely, heart failure with preserved ejection fraction is characterized by excessive myocardial fibrosis and cardiomyocyte hypertrophy that cause reduced left ventricular relaxation. Both heart failure subtypes cause identical symptoms and signs. Clinical and laboratory tests assist in the diagnosis of systolic heart failure or heart failure with preserved ejection fraction (diastolic heart failure) and can help in the identification of different causes of the disease and comorbidities. In the last two decades, the renin-angiotensin system (RAS) has been identified as a crucial regulator in all phases of systolic and diastolic heart failure. Although several studies are needed to further clarify this issue, three different levels (systemic, intracardiac and intracellular) for renin pathophysiological activity have been identified. In particular, the direct role of intracellular renin on subcellular cardiomyocyte remodeling could be considered as a very fruitful investigation field. Several ongoing clinical studies will probably clarify the role of renin inhibitors in heart failure. The ancient theory of Skeggs and coworkers on direct renin inhibition to block the RAS cascade effects could be confirmed in future studies.