Senescence was initially described by Leonard Hayflick, proposing that normal primary cells gradually loose their proliferative potential and this was latter linked to telomere shortening. Senescence is also activated by chemotherapy treatment or by oncogenic insults as illustrated by the Ras oncogene that induces a definitive proliferation arrest in primary cells. 1 This sup-pressive mechanism has been described in vivo, either in animal models, in the early steps of carcinogenesis as shown for Braf-driven melanomas 2 or in response to chemotherapy. 3 Senescence is often a consequence of DNA damage, induced either by chemotherapy or by replicative stress. This results in the up-regulation of the p53-p21 and p16-Rb pathways, leading to Rb activation and the inhibition of E2F proliferative genes within heterochromatin foci named SAHFs. The regulation of the p53-p21 axis is well characterized and mostly mediated by ATM/ATR/Chk1/2 signaling. p16INK4 upregulation remains less understood although elegant experiments have described its epigenetic regulation by the EZH2 and JMJD3 proteins. Although arrested, senescent cells exert a profound influence on their microenvironment through the production of a specific secretome or SASP (Senescence Associated Secretory Phenotype). Depending on the context, the SASP can reinforce senescence through an autocrine loop or promote oncogenic features such as migration and EMT. Recent results have described the importance of the NF-kB and CEBP transcription factors and of the mTOR pathway in the activation of this secretome. Through IL1alpha translation and regulation of the ZFP36L1 RNA binding protein, mTOR regulates the expression of several components of the SASP. These autocrine and paracrine influences raise questions about the value of senescence as a tumor suppressive mechanism, in particular as compared to apoptosis. Recent results have shown that the elimination of p16INKA-expressing cells reduces tumorigene-sis and organ deterioration during aging. 4 Important results have described that senescence can be incomplete and that melanoma cells restart proliferation following PTEN depletion. 5 Using colo-rectal cells, we have recently shown that senescence escape leads to the emergence of more transformed cells that depend on the Akt-Mcl1 pathway. In a recent study, Cahu, Sola and colleagues observed the same effect on myeloma cells. When irradiated or treated with doxorubicin, these cells enter senescence. As a consequence of DNA damage they produce a SASP that allows the emergence of cancer stem cells. One of the important conclusion of this work was that the cooperation between senescent and initiating cells is involved in myeloma relapse. In a more recent work, 6 they investigated the early response of myeloma cells, following their hypothesis that targeting cancer cells before senescence induction would be beneficial by 1) reducing the secretion of survival factors 2) preventing the emergence of cancer stem cells involved in tumor relapse. According to previous studies, 7 they used mTOR inhibitors or hypoxia induction to prevent senescence and effectively observed that this inhibited p21waf1 and reduced cell cycle arrest induced by C-ion irradiation. Interestingly, this was correlated with the up-regulation of the RAD50 gene. RAD50 is part of the MRN complex which is involved in DNA repair via homologous recom-bination. In response to C-ion irradiation, RAD50 is normally down-regulated and the authors proposed that this favors genomic instability by maintaining a low level of DNA damage. Incomplete repair induces cell cycle arrest and senescence but at the same time allows cell adaptation and the emergence of cancer initiating cells. Whether RAD50 down-regulation is necessary for senescence induction remains to be determined but it is known that this sup-pressive mechanism is correlated with DNA damage. These observations raise an interesting question about the consequences of using DNA repair inhibitors in clinical setting. Combined with genotoxic treatments, drugs targeting chk1/2 kinases or brca1/2 for instance are expected to induce cell death through mitotic catastro-phy. In front of these sustained damages, it will be interesting to determine if senescence can still function as an adaptive mechanism to DNA-repair targeting drugs and if this allows the emergence of a small population of more aggressive cells. Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed. Reference [1] Perez-Mancera PA, Young AR, Narita M. Inside and out: the activities of senescence in cancer. Nat Rev Cancer 2014; 14:547-58; PMID:25030953; http://dx.