K-ras is currently accepted to be the most frequently mutated oncogene in non-small cell lung cancer. In addition, tumors harboring mutant K-ras seem to be refractory to most available systemic therapies, making K-ras an attractive target for cancer therapy. The complexity of K-ras signaling presents many opportunities for therapeutic targeting. A number of different approaches aimed at abrogating K-ras activity have been explored in clinical trials. Several of the putative K-ras-directed therapeutic agents tested have demonstrated clinical activity. However, many of these agents have multiple targets, and their antitumor effects may not be due to K-ras inhibition. To date, no selective, specific inhibitor of the K-ras pathway is available for routine clinical use.