Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of beta-blockers and antagonists of the renin-angiotensin system, there is still a major unmet need for better therapies for many patients with heart failure. However, disappointment related to late-stage clinical failures of a number of novel agents, including endothelin antagonists and tumour-necrosis factor blockers, has reduced the impetus of drug development in this field. Here, we review possible targets for heart failure therapy that have emerged from recent progress in our understanding of the underlying disease mechanisms, and highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.