Heart failure is a major public health problem, associated with significant morbidity and mortality. Over the years several pathophysiological models of heart failure have been proposed, that led to the development of specific therapeutical agents. Hyperactivation of the renin-angiotensin-aldosterone, neurohormonal and adrenergic system are well known pathophysiological pathways involved in heart failure development. Several drugs have been developed to address these changes, resulting in an improvement in life expectancy. Sodium-glucose co-transporter 2 inhibitors completed the heart failure foundational therapy, through mechanisms not fully understood. Nevertheless, the puzzle is not complete and the patients are still exposed to a residual risk of adverse events or worsening heart failure, so that new pathways, new therapeutic targets and development of adjunctive structural interventions are still required.