GpIbalpha, a subunit of the von Willebrand factor receptor, functions during blood clotting to promote platelet adhesion and activation. GpIbalpha is widely expressed, is positively regulated by c-Myc and is essential for the promotion of c-Myc-mediated chromosomal instability. We now show that GpIbalpha is also a classical oncoprotein in which its deregulated expression leads to transformation, reduced growth factor requirements, increased resistance to apoptosis, and, in primary cells, p53-dependent senescence. Finally, GpIbalpha also promotes double-stranded DNA breaks, and induces profound nuclear dysmorphology, indicating that, in addition to its direct transforming function, it displays genotoxicity at several distinct levels. These findings identify novel functions for GpIbalpha and pathways through which c-Myc mediates transformation and global genomic destabilization.