Transgenic mice carrying single cancer-generating genetic mutations are useful models for inherited cancers, but do not adequately model cancers that arise spontaneously. Tyler Jacks and colleagues at the Howard Hughes Medical Institute (Cambridge, MA) and Massachusetts Institute of Technology (Boston, MA) have now applied the so-called hit-and-run gene-targeting approach to generate a mouse prone to sporadic cancers such as lung cancer (Nature, 410, 1111–1116, 2001). The researchers generated constructs of a “silent” K-ras gene—an oncogene known to be associated with lung, pancreatic, and colon cancers. The silent gene was incorporated at its normal genomic location in mouse stem cells, creating a hybrid gene (the “hit”). In the adult transgenic animals, spontaneous recombination events take place (or “run”), shuffling mutant and wild-type K-ras DNA segments, and occasionally giving rise to mutant K-ras that promotes cell proliferation. Recombination events are rare and random, and so K-ras is expressed diffusely in cells scattered around the body. In particular, K-ras mutations gave rise to lung cancers, although lymph and skin cancers were also common. The mouse could provide a useful test model for chemotherapeutics and improved understanding of lung cancer pathophysiology.