Rationalized cancer therapy aims at blocking overactive signaling pathways in cancer cells using kinase inhibitors. Essential for its success is the identification of suitable drug targets. Several recent reports have shown that by using control analysis, one can determine which component of a pathway is in control of its output. However, it has not been analyzed how a mutation in an oncogene affects the extent to which the various components are important. Are the same proteins still important after an oncogene has been activated? In the present study, we show that, upon mutation, oncogenes such as mutant kinases tend to lose part of their control on signaling. On the other hand, some of the nonmutated genes may become more important, when compared to the situation before the mutation. This may imply that, perhaps paradoxically, signaling proteins encoded by nonmutated genes should make better drug targets against cancer. © 2006 Humana Press Inc. All rights of any nature whatsoever reserved.