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Senior cardiologists can recall the evolution of cardiologists’ views on heart failure (HF) pathophysiology and treatment approaches during their professional career. Milton Packer has recently formulated the progress of HF concepts in four stages: 1) the cardiorenal model (1940s through the 1960s), 2) the cardiocirculatory model or hemodynamic hypothesis (1970s and 1980s), 3) the neurohormonal model (from 1990s up to recently), and 4) the recent cellular stress model. The cardiorenal model relied on digitalis and diuretics. Vasodilators and positive inotropes were viewed with hope at the time of the prevalence of the hemodynamic hypothesis, but did not meet expectations. Only the neurohormonal model with renin-angiotensin-aldosterone system inhibitors and beta-blockers as acting drugs provided permanent improvement in substantial clinical outcomes, including death rates. However, those treatments were ineffective in heart failure with preserved ejection fraction (HFpEF), comprising half of all patients with HF. The serendipitous discovery that sodium-glucose cotransporter-2 (SGLT2) inhibitors, first introduced as antidiabetic drugs, have beneficial cardiac effects, led to clinical trials which proved substantial outcome benefits not only in heart failure with reduced ejection fraction but also in HFpEF. As the mystery shrouding the mechanisms of sodium-glucose cotransporter 2 inhibitors actions began to be unraveled, the cellular stress model of HF was introduced. This review is focused on historical and recent HF pathophysiological concepts, along with the drugs associated with them, but non-pharmacological treatments are also addressed. Finally, the prospects for advancements in the understanding and treatment of HF are also discussed. [ABSTRACT FROM AUTHOR]