Permanent loss of heart muscle cells, cardiomyocytes, is a major mechanism resulting in ventricular dysfunction and heart failure. Potential solutions to this problem could be either to stimulate the heart to generate new cells by inducing existing cardiomyocytes to divide or to activate or deliver stem cells/ progenitor cells to multiply and subsequently differentiate into cardiomyocytes. Utilizing in vitro and in vivo approaches, p38 MAP kinase has recently been identified as a key negative regulator of cardiomyocyte proliferation. This work provides strong evidence that adult mammalian cardiomyocytes can divide. This review discusses the potential of the induction of mammalian cardiomyocyte proliferation as a therapeutic strategy for myocardial repair.