Characterizing the mutations that occur during the evolution of tumors is a major challenge. Understanding whether cancers arise from monoclonal or polyclonal cells and determining the rate and progression of mutation accumulation are important areas of cancer research. Now, Jun Wang and colleagues report the first single-cell cancer exomes. Their first study (Cell 148, 873–885, 2012 ) reports exome sequencing of 82 bone marrow cells and 8 oral mucosal cells from a hematopoietic neoplasm called essential thrombocythemia (ET). The authors performed wholegenome amplification and sequenced targeted exome regions at 30× coverage. They calculated that the average allele dropout (where amplification failed in one allele) was 43%, and the false discovery ratio was 6.0 × 10−5. As a mutation found in only one cell is likely to be a false positive, only mutations present in at least five cancer cells are considered to be somatic mutations. The authors identified 712 somatic point mutations and performed principal-component analysis, which showed that the ET cells were distinct from the oral mucosal cells, suggesting a monoclonal origin for ET cells. The second study by these authors (Cell 148, 886–895, 2012 ) reports exomes of 25 cells from an individual with clear cell renal cell carcinoma.