A solid tumor contains millions of cells. Understanding the origin and evolution of tumor cells can help in the development of effective treatments. To investigate intratumor heterogeneity with new genomic tools, such as exome sequencing, one can use a tour-de-force single-cell approach or undertake regional analysis. Charles Swanton and colleagues report a multiregional analysis of four primary renal carcinomas and associated metastases (N. Engl. J. Med. 366, 883–892, 2012). Using exome-sequencing data from nine regions of the nephrectomy specimens and metastases, they constructed tumor phylogenetic trees from two patients. In both tumors, the trees showed a branched evolution pattern and distinct metastasis clusters. Only one-third of somatic mutations were shared across all regions, whereas region-specific, 'private' mutations accounted for 22–53% of nonsynonymous point mutations and insertions and/or deletions. Analysis of histone marks suggested functional convergence, despite divergent mutations in the chromatin modification genes SETD2 and KDM5C. Genetic and functional heterogeneity was also observed for a mutation affecting mammalian target of rapamycin (mTOR) and its downstream effectors. This study sheds light on the mechanism of Darwinian tumor adaptation and on the potential for personalized medicine targeting mutations at the trunk of a tumor's phylogeny.