Mutational activation of the K-ras gene is a frequent oncogenic event in human cancers, associated with poor clinical prognosis and resistance to treatment. Despite efforts to develop therapeutics that target K-ras or its downstream effector molecules, clinical benefit in this setting has not yet been achieved. An alternative approach to K-ras mutant cancers involves the identification of genes that selectively drive the maintenance of tumors that are “addicted” to or dependent on mutant K-ras. Disruption of these genes would result in “synthetic lethality” specifically in cancer cells driven by mutant K-ras, thereby potentially sparing non-tumor cells. Through this approach, three recent reports have identified PLK1, STK33, SYK, RON and integrin β6 as previously unappreciated pharmacologically tractable targets in the setting of K-ras activation, which drive growth and survival selectively in K-ras-dependent cancer cells.