Epithelial stem cells are typically multipotential and are likely the cell of origin of epithelial cancers. Tracing the expansion of a single stem cell’s progeny, identifying and characterizing these cells in human tissue has proven difficult. Invasive labeling studies, which have led to much success in model organisms, are impracticable in humans. Instead, human studies must rely upon naturally occurring clonal markers : typically somatic DNA alterations that uniquely identify a population of cells with the same ancestry. In normal epithelium, nonpathogenic mitochondrial DNA mutations have proven useful. In premalignant and malignant disease, genomic DNA mutations within tumor suppressor genes or oncogenes can be used to trace the spread of mutant clones.