A simple view of cancer is that cells become transformed because they acquire critical mutations that release them from growth constraints and allow them to become invasive. But are things that simple - can genetically normal cells become cancerous? On p. 1495, Maricel Maffini and co-workers provide strong evidence that epithelial cells can become malignant as a consequence of alterations in surrounding tissue rather than mutations in their own DNA. Using a tissue recombination model that allows easy separation of epithelium and neighbouring stromal cells, the authors exposed epithelial cells to the carcinogen N-nitrosomethylurea (NMU) in vitro and then transplanted them into rat mammary gland fat pads lacking epithelium (cleared fat pads). They also did the reverse, transplanting unexposed epithelial cells into cleared fat pads of rats previously exposed to NMU. Strikingly, neoplastic transformation of the epithelial cells occurred only when the stroma had been exposed to NMU. Maffini and co-workers therefore propose that the stroma is the target of the carcinogen and that alterations in its behaviour are necessary and sufficient to induce transformation of the neighbouring epithelium. In a Cell Science in Context article on p. 1287, Valerie Weaver and Penney Gilbert discuss this idea in the context of recent studies that suggest that cancer is perhaps better viewed as a disease of tissue organization rather than one caused by accumulation of mutations in individual cells.