Somatic genetic alterations provide the foundation for the evolution of human tumors as well as significant opportunity for therapeutic intervention. This review will cover the growing list of examples where somatic genetic alterations have successfully been coupled with a targeted agent resulting in positive clinical outcome. For example, recent data from randomized clinical trials support the earlier observations that EGFR mutant lung tumors are most likely to respond to EGFR kinase inhibitors, while wild-type tumors rarely respond. Emerging data indicate that this principle may also apply to such intractable diseases such as melanoma which has long been refractory to conventional chemotherapeutics.