Cancer is essentially a genetic disease. Recent high-throughput mutational analyses of gene families in human colorectal, breast and lung cancer, myeloproliferative disorders, and other tumor types have identified a number of kinases and phosphatases that are mutated in the human cancer genome. This approach has been proven to be an efficient way to catalog tumor-specific mutations in human cancers. Although there are still some technical hurdles to overcome, it is not a far-reaching goal to perform genome-wide mutational analysis in all different tumor types. Systematic cataloging of tumor-specific mutations in the human cancer genome not only will lead to new insights into the mechanisms of tumorigenesis, but also provide unprecedented opportunities in the design of novel therapeutics for cancer patients. Personalized cancer therapy based on tumor-specific mutations will be a realistic goal in the near future.