Unfortunately, the first generation of RAF inhibitors showed high rates of drug resistance and subsequent analysis of the underlying resistance mechanisms uncovered a paradoxical hyperactivation of ERK, either through increased activation of WT RAF dimers in BRAF mutant cancers, or by transactivation of the drug-free RAF molecule after binding of the inhibitor to the other RAF monomer within a dimer [187,188]. The gene discussed is BRAF; the disease is cancer.