The Merkel cell polyomavirus (MCPyV), discovered in 2008, drives the development of most Merkel cell carcinomas (MCCs) through several canonical mechanisms. A glaring gap in our knowledge remains the basis by which MCPyV, among all 12 human polyomaviruses, is the only one that causes cancer in humans. Moreover, initial attempts by numerous groups have failed to reproduce MCC in mice using oncoproteins from this polyomavirus. Verhaegen et al. report MCPyV small T-antigen-expressing transgenic mice that now provide insight into in vivo transformation mechanisms.