ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors. •All activating BRAF mutants are RAS independent•Activating BRAF mutants signal as active monomers or constitutive dimers•RAF dimers are insensitive to clinical RAF inhibitors due to negative cooperativity•A compound that equally inhibits mutant BRAF monomers and dimers overcomes resistance Yao et al. show that RAS-independence is a common property of activating BRAF mutants that occurs by either of two mechanisms. Active monomers are sensitive to current drugs, whereas constitutive dimers are not. A compound that equally binds both sites of dimers is active against all activated BRAF mutants and overcomes acquired resistance to current drugs.