The present invention provides methods and compositions for the detection of novel BRAF splice variants that mediate resistance to BRAF and/or pan-RAF inhibitors. In particular, the invention provides PCR primer(s) to be used in the disclosed methods of detection. In some embodiments, the compositions and methods of the present invention are used to predict resistance to BRAF and/or pan-RAF inhibitors in a subject suffering from or suspected of having cancer and further provides alternative treatment strategy(ies) for a subject predicted to be resistant to BRAF and/or pan-RAF inhibitors. In a further embodiment, methods and composition for the identification of novel agents useful to overcome resistance to BRAF and/or pan-RAF inhibitors are disclosed. The present invention also provides isolated polynucleotide sequences of novel 5′ BRAF splice variant(s) and proteins produced from such polynucleotide sequences as well as cell line(s) that endogenously or exogenously express the splice variant(s).