improving net pump function and are currently in phase 2 clinical trials (NCT00624442). Another approach stems from the discovery that the reduced form of nitric oxide (nitroxyl, or HNO) enhances cardiac contraction independently of cAMP-PKA or cGMP signaling, improving Ca2+ cycling and enhancing myofilament Ca2+ sensitivity by modifying crucial thiol groups on proteins such as phospholamban12. Clinical drug development is now underway. Although the legacy of clinical trials like those with levosimendan can be viewed specifically; to paraphrase Tolstoy, all unsuccessful trials are unsuccessful in their own way; they have reminded us that the search for a successful contractility drug is daunting. But many in the field remain convinced the goal is achievable, inspiring new work at the bench to figure out how CRT does it and to discover new pathways to more safely and effectively counteract heart failure.