The fundamental role of E2F transcription factors in the regulation of proliferation is well established. According to a widely accepted model, E2F1, E2F2, and E2F3 are classified as "activating" E2Fs since they induce proliferation of quiescent cells whereas E2F4 and E2F5 do not have the power to incite cell cycle progression but are related to differentiation processes and were therefore considered to be "repressive". In addition, it has been postulated that "activating" E2Fs induce apoptosis in a wide variety of cell types depending on their expression level. However, we demonstrated recently that this 'threshold model' does not hold true for cardiomyocytes. In a series of experiments in which we overexpressed individual E2Fs we found that directed expression of E2F2, unlike E2F1, E2F3 and E2F5, did not induce apoptosis but even suppressed expression of several pro-apoptotic genes in primary cardiomyocytes. Furthermore, we established that not only E2F1, E2F2, and E2F3 but also E2F4 was able to induce S-phase entry of primary cardiomyocytes. Our results suggest that it is possible to utilize the proliferation-inducing properties of the E2Fs in cardiomyocytes without activation of potentially harmful pro-apoptotic traits. This finding might open a new access to stimulate regeneration in postmitotic tissues such as the heart.