Abstract Sorafenib is U.S. Food and Drug Adminstration–approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal–regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor–induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun–NH2–kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif–containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis. Mol Cancer Ther; 13(1); 221–9. ©2013 AACR.