Vemurafenib recently achieved FDA approval for treating patients with metastatic melanoma harboring the BRAF V600E mutation. The BRAF^V600E-driven uncontrolled proliferation is effectively blocked by vemurafenib, reflected in the remarkable regressions observed in the clinic. However, most patients eventually relapse, and in many instances, progression is associated with reactivation of ERK signaling, as observed by high levels of ERK phosphorylation in tumor biopsies taken at progression. The cover shows an example of a tumor biopsy taken at progression. Su and colleagues identify a novel KRAS mutation that mediates the acquired resistance of melanoma cells to vemurafenib. Both MAPK and PI3K pathways are active despite the presence of drug. Combinations of vemurafenib with either MEK or AKT inhibitors are able to overcome this resistance, providing hope that these combinations could mitigate disease relapse in patients. For details, see the article by Su and colleagues on page 969 of this issue.