Heart failure (HF) is a debilitating condition characterized by the heart's inability to pump sufficient blood to the body's organs and represents one of the largest global health concerns. Despite the high incidence of mortality and increasing patient population, approvals of new HF therapies have been surprisingly limited with only two approved in the last 15 years. Given the lack of new medications, a significant number of companies and institutions have remained committed to identifying novel small molecules for HF. This article provides an overview of the current HF landscape as well as the recent medicinal chemistry efforts toward future therapies.