Numerous oncogenic mutations occur within the BRAF kinase domain (BRAFKD). Here we show that stable BRAF-MEK1 complexes are enriched in BRAFWT and KRAS mutant (MT) cells but not in BRAFMT cells. The crystal structure of the BRAFKD 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. Display omitted •BRAF-MEK1 complexes are enriched in the cytosol of BRAFWT and KRAS mutant cells•The crystal structure of BRAF with MEK1 reveals a face-to-face complex•Oncogenic BRAF mutations modulate complex formation through distinct mechanisms•BRAF inhibitors can block signaling by sequestering a dormant BRAF-MEK1 complex Based on structural and biochemical data, Haling et al. show that BRAF:CRAF dimerization, instead of MEK1:BRAF interaction, is the rate-limiting step in the RAF/MEK pathway activation. BRAF activating mutants either enhance BRAF:CRAF or BRAF:BRAF dimerization or completely bypass the requirement of dimerization.