The poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) family of proteins includes 17 members in mammals, most of which are enzymes that are responsible for catalysing the addition of poly ADP-ribose units to different substrates. To date, the characterised function of ADP-ribosylation is related with its crucial role in DNA repair, which has led to the use of PARP inhibitors in the therapeutic management of several types of cancer. This is especially relevant in tumours associated with mutations in one copy of either the BRCA1 or BRCA2 genes. In these tumours, treatment with PARP inhibitors (PARPi) causes an increase in DNA single-strand breaks, which may be converted into irreparable toxic DNA double-strand breaks during replication, resulting in cell death, a mechanism known as synthetic lethality. Unfortunately, despite the enthusiasm generated by the initial reports of PARPi-mediated synthetic lethality in BRAC-deficient cells, late studies have produced disappointing results, thus reinforcing the need for understanding the mechanisms underlying this phenomenon. In this respect, it is important to take into consideration that, in addition to their key role in DNA repair, several studies suggest that PARP proteins, and specifically PARP1, may also act through mechanisms that do not relay on its enzymatic activity. This growing knowledge on PARP1 biology has provided new clues in the search for novel mechanisms to support the use of PARPi in the treatment of cancer, including a possible role in regulating E2F1 transcriptional activity.