Tumor cells contain multiple mutations, yet they often depend on continued expressed of a single oncoprotein for survival. Targeting these proteins has led to dramatic responses. Unfortunately, patients usually progress, through drug resistance or adaptive resistance through reprogramming of signaling networks. The Ras-MAPK pathway provides examples of these successes and failures, and has revealed unexpected degrees of oncogene addiction and signaling complexity that are likely to be useful lessons for the future of targeted therapy. J. Surg. Oncol. 2011;103:464–467. © 2011 Wiley-Liss, Inc.