(V600)BRAF mutation was identified as an ideal target for clinical therapy due 
to its indispensable roles in supporting melanoma initiation and progression. 
Despite the fact that BRAF inhibitors (BRAFi) can elicit anti-tumor responses in 
the majority of treated patients and confer overall survival benefits, acquired 
drug resistance is a formidable obstacle to long-term management of the disease. 
Several aberrant events including RTK upregulation, NRAS mutation, mutant BRAF 
amplification or alternative splicing, and MEK mutation have been reported as 
acquired BRAFi resistance mechanisms. Clinially, detection of these resistance 
mechanisms help understand drug response patterns and help guide combinatorial 
therapeutic strategies. Therefore, quick and accurate diagnosis of the resistant 
mechanisms in tumor biopsies has become an important starting point for 
personalized therapy. In this chapter, we review the major acquired BRAFi 
resistance mechanisms, highlight their therapeutic implications, and provide the 
diagnostic methods from clinical samples.