PLX8394 is a potent and selective Raf inhibitor, with an IC50 of appr 5 nM for BRAFV600E. PLX8394 potently inhibits phosphorylation of ERK1/2 in PRT #3 and PRT #4 cells at >25 nM and in addition to parental cells at 10 nM. PLX8394 effectively reduces cyclin D3 and cyclin D1, phosphorylation of retinoblastoma protein, and expression of cyclin A2 in parental cells and PRT #3 and PRT #4 cells. PLX8394 inhibits ERK1/2 phosphorylation and the growth of vemurafenib-resistant cells harboring either a BRAF V600K/L505H double mutation or an transposon-induced, N-terminal truncated form of BRAF. PLX8394 significantly impairs tumor cell growth and suppresses MAPK signaling in LA cell lines expressing either endogenous V600E or non-V600 mutant forms of BRAF. PLX8394 (150 mg/kg/d) substantially suppresses tumor growth, MAPK pathway signaling and tumor cell proliferation in these H1755 xenograft tumors without overt toxicity in mice. PLX8394 combines with erlotinib yields plasma erlotinib concentrations of >1 μM.