This review provides a novel perspective on the challenges of translating cardioprotection to the clinic, and present the case that optimal cardioprotection may require the combination of additive or synergistic multitarget therapies. This paper emerged as a consequence of a significant grant awarded to the Hatter Cardiovascular Institute by the European Union. J Am Coll Cardiol. 2019 Jan 8;73(1):89-99. doi: 10.1016/j.jacc.2018.09.086