Although ideas on the stem cell origins of cancer date more than one hundred years, critical evidence to support these theories is largely lacking. Our objective here is to outline our historical perspective on keratinocyte stem cells in the cutaneous epithelium and to summarize specific evidence suggesting that epithelial stem cells may contribute to chemically induced skin cancer. We note that, while strong evidence does support this hypothesis, experiments in progress may provide direct visualization of tumors derived from hair follicle stem cells.