The ability of cells to maintain genomic integrity is fundamental for protection from cancer development. Genomic instability characterizes almost all sporadic human cancers, although mechanisms causing it are still not well understood. High-throughput sequencing studies suggest that mutations in DNA repair genes do not account for the presence of genomic instability in many sporadic cancers (Negrini et al 2010). Alternatively, activation of oncogenes, and more generally of growth signaling pathways, has been shown to induce genomic instability in mammalian cells cultured in vitro and in mouse models (Hernando et al 2004, Negrini et al 2010). Hyperactive Shh pathway activity has been shown to induce genomic instability and the development of spontaneous and ionizing radiation (IR)-induced tumors (Leonard et al 2008). Now we show that high levels of YAP expression further contribute to generation of genomic instability since irradiated YAP-expressing cells present a higher number of chromosomal alterations. The role of genomic instability has remained a controversial issue in cancer biology. Although it is still unclear if it is necessary for tumorigenesis to occur, genomic instability certainly provides the tumor with an advantage in terms of faster progression through the many stages of tumorigenesis (Sieber et al 2003). Indeed, we show that ectopic expression of YAP accelerates medulloblastoma onset and produces tumors that are highly aggressive and rapidly lethal.