The demonstrated genomic heterogeneity of human cancers is having major impacts on the development and evaluation of cancer therapeutics and molecular diagnostics. Many new cancer drugs target somatic alterations in tumors and are being developed with companion diagnostics. Oncology drug development and practice are likely to become increasingly stratified and utilize the enrichment Phase III trial paradigm. Although this paradigm includes an increasing number of successes, single-agent molecularly targeted treatment of metastatic disease will generally provide limited patient benefit. More substantial gains will require better understanding of crosstalk among signaling pathways, ability to combine drugs and use of drugs at initial diagnosis. Early phase discovery clinical trials in which patients will have genome-wide tumor characterization at diagnosis and at critical retreatment points will provide data sets for learning how to effectively match therapeutics to genomic alterations. However, moving tumor genomics to clinical oncology entails many practical challenges. We review some of these challenges and the clinical studies that are being undertaken to translate genomics to clinical oncology.