RAF inhibitors, such as vemurafenib, are effective in treating melanomas with the BRAF(V600E) mutation but often lead to resistance. This study identifies a novel resistance mechanism involving aberrantly spliced BRAF(V600E) variants. These variants lack exons 4-8, including the RAS-binding domain, and exhibit enhanced dimerization in cells with low RAS activation. This dimerization allows the variant to resist RAF inhibitors, as it can activate ERK signaling independently of RAS. The study shows that in resistant melanoma cells, the splicing variant p61BRAF(V600E) is expressed, and its dimerization is critical for resistance. Mutations that disrupt dimerization restore sensitivity to vemurafenib. The findings suggest that resistance arises from the expression of BRAF(V600E) splicing variants that dimerize independently of RAS. These variants were detected in six of 19 patients with acquired resistance to vemurafenib. The study also demonstrates that MEK inhibitors can be effective in combination with RAF inhibitors to overcome resistance. The results highlight the importance of BRAF splicing variants in RAF inhibitor resistance and suggest that targeting downstream components of the pathway, such as MEK, may be a viable strategy to delay or prevent resistance.RAF inhibitors, such as vemurafenib, are effective in treating melanomas with the BRAF(V600E) mutation but often lead to resistance. This study identifies a novel resistance mechanism involving aberrantly spliced BRAF(V600E) variants. These variants lack exons 4-8, including the RAS-binding domain, and exhibit enhanced dimerization in cells with low RAS activation. This dimerization allows the variant to resist RAF inhibitors, as it can activate ERK signaling independently of RAS. The study shows that in resistant melanoma cells, the splicing variant p61BRAF(V600E) is expressed, and its dimerization is critical for resistance. Mutations that disrupt dimerization restore sensitivity to vemurafenib. The findings suggest that resistance arises from the expression of BRAF(V600E) splicing variants that dimerize independently of RAS. These variants were detected in six of 19 patients with acquired resistance to vemurafenib. The study also demonstrates that MEK inhibitors can be effective in combination with RAF inhibitors to overcome resistance. The results highlight the importance of BRAF splicing variants in RAF inhibitor resistance and suggest that targeting downstream components of the pathway, such as MEK, may be a viable strategy to delay or prevent resistance.