The therapeutic heart failure armamentarium has evolved from drugs to transplantation to devices through further understanding of its complex pathophysiology and pathogenesis. Current medications capitalize on our evolving understanding of the sympathetic and renin-angiotensin-aldosterone systems that subsequently promote both beneficial and maladaptive responses that ultimately yield a decrease in cardiac function. Despite these advancements, the prevalence of heart failure continues to rise and carries a significant burden on our patients and health care system. This presents a clinical dilemma on how best to care for a growing, complex, and heterogeneous cohort. Ideal treatments should decrease morbidity and mortality while providing an improvement in quality of life and functional capacity. New interventions will continue to become incorporated into everyday practice, but awareness and prevention should remain the mainstay followed by optimization of guideline-directed therapies. It is equally important to individually tailor our therapeutic approach. While strategies to treat heart failure with reduced ejection fraction continue to advance, our understanding of how best to treat specific etiologies remain in question. This review will focus on current and proposed novel interventions for the management of chronic, systolic heart failure including angiotensin receptor-neprilysin inhibitor, I_f channel antagonist, sodium-glucose cotransporter-2 inhibitors, and oral potassium binders.