Despite therapeutic advances that slow its progression, heart disease remains the world's leading cause of death. Until recently, the "Holy Grail" of cardiac biology, to regenerate the damaged heart, appeared to be a fantastical and quixotic quest. However, recent studies showing that the mammalian heart possesses an innate, albeit limited, regenerative capacity offer hope that effective cardiac regeneration may be an attainable goal. This Special Issue of Stem Cell Research reviews the remarkable progress that has been made in this field in the last few years. (C) 2014 The Authors. Published by Elsevier B.V.