Growing evidence links the Hedgehog signaling pathway to a wide range of human cancers, most of which arise sporadically. We report a novel somatic mouse cancer model and utilize this to survey Hedgehog-dependent sporadic tumors. By spontaneous and regulated recombination-mediated activation of an oncogenic form of Smoothened (SmoM2), we modulate tumor spectrum, frequency, and latency. Transcriptional profiling reveals a core expression signature in these diverse tumors. The cover image shows strong expression of PDGFRa in a medulloblastoma and rhabdomyosarcoma, two tumors resulting from SmoM2 activity. This model provides a robust tool for mechanistic dissection and treatment of Hedgehog-dependent tumors. More generally, the approach provides a genetic platform for identifying tumorigenic potential in either candidate oncogenes or tumor suppressors, as well as for the effective modeling of sporadic cancers. For details, see the article by Mao et al. on page 10171 of this issue.