Unchecked cell growth is a hallmark of cancer. During oncogenesis, cancerous cells become resistant to the TGF-β signaling pathway that usually keeps cell growth in check. The role of a critical mediator of this pathway, Smad4, in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this issue of the JCI, Bornstein and colleagues report that Smad4 expression is decreased in malignant HNSCC and, surprisingly, also in normal-appearing buccal mucosa adjacent to HNSCC (see the related article beginning on page 3408). They also show that targeted conditional deletion of Smad4 in the head and neck epithelium of mice is alone sufficient to initiate spontaneous HNSCC, in conjunction with DNA repair gene dysregulation, genetic instability, and inflammation. These findings point to a novel function for Smad4 as a guardian gene that maintains genomic stability.