CCT196969 is a novel orally available, pan-RAF inhibitor with anti-SRC activity. CCT196969 blocked growth of BRAF-mutant and NRAS-mutant melanoma cells, inhibiting MEK–ERK, in vitro and in vivo. CCT196969 also prevented growth of xenografts derived from patient tumours with acquired or intrinsic resistance to BRAF and MEK inhibitors. BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs.