The cellular transcription factor E2F1 is part of an anti-tumor safeguard mechanism: it engages cell-death pathways either alone or in cooperation with p53 to protect organisms from the development of tumors. E2F1 activates downstream factors, which in turn produce secondary changes in gene expression that trigger apoptosis. Although the mechanisms are incompletely understood, several studies have demonstrated that E2F1 is involved in many different aspects of programmed cell death depending on the cellular background. Here, these findings are highlighted in the context of the most recent follow-up studies that have used apoptotic E2F1 genes as new therapeutics or drug targets, thereby providing insight into the basic mechanisms of E2F1-induced apoptosis and its possible clinical implications.