Summary Numerous oncogenic mutations occur within the BRAF kinase domain (BRAF KD ). Here we show that stable BRAF-MEK1 complexes are enriched in BRAF WT and KRAS mutant (MT) cells but not in BRAF MT cells. The crystal structure of the BRAF KD in a complex with MEK1 reveals a face-to-face dimer sensitive to MEK1 phosphorylation but insensitive to BRAF dimerization. Structure-guided studies reveal that oncogenic BRAF mutations function by bypassing the requirement for BRAF dimerization for activity or weakening the interaction with MEK1. Finally, we show that conformation-specific BRAF inhibitors can sequester a dormant BRAF-MEK1 complex resulting in pathway inhibition. Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK. [ABSTRACT FROM AUTHOR]