Metastatic cancers are considered to emerge from a multistep mutagenesis process that drives disease progression. However, evidence is emerging that even cancer types with single mutations can progress from benign precursor lesions to metastatic disease, implicating non-genetic mechanisms in this process. In cutaneous squamous cell carcinoma (SCC) for example, the mechanisms by which a single oncogenic mutation in a stem cell drives disease progression from benign papillomas to invasive disease are unclear. Yuan et al. now delineate the complex crosstalk between cancer stem cells (CSCs), located at the tumour–stromal interface, and their microenvironment and demonstrate that these interactions drive disease progression in cutaneous SCC.