E2F1 is involved in both cell cycle and apoptosis, but we still fail to understand whether these are distinct E2F1 states and what controls the transition between states. Studies in cell cultures are often contradictory showing opposite effects of E2F1; even further, some phenotypes in animals lacking or overexpressing E2F1 would not be predicted from in vitro findings. In this review, we analyze current literature on the role of E2F1 in apoptosis and use engineering concepts and a systems biology approach to align the overwhelming amount of contradictory data on this gene.