Heart failure is a major disease burden worldwide, and its incidence continues to increase as premature deaths from other cardiovascular conditions decline. Although the overall molecular portrait of this multifactorial disease remains incomplete, molecular and genetic studies have implicated, in recent decades, various pathways and genes that participate in the pathophysiology of heart failure. Here, we highlight the current understanding of the molecular and genetic basis of heart failure and show how recently developed genomic tools are providing a new perspective on this complex disease.