Transcriptional inhibitors (TI) repress global transcription and induce apoptosis. It has been suggested that induction of p53 is one of the hallmarks of global transcriptional repression. Two recent papers suggested that treatment of human cancer cells with TIs, leads to p53-dependent, transcription-independent or p53-dependent, transcription-dependent apoptosis. The latter mechanism is linked to the fact that TIs can be selective in their inhibitory effects thereby permitting transcription of some genes. However, the majority of other published data suggest that these drugs induce p53-independent apoptosis. In this article I discuss the mechanisms of TI-dependent cell death and the potential role of p53 in this process.