The Ras-specific guanine nucleotide exchange region of hSos1 consists of two consecutive domains: the catalytic core (residues 742-1024) contains all residues binding to Ras, including the catalytic hairpin, and an upstream REM domain (residues 553-741), so called because it contains an evolutionary conserved Ras Exchange Motif (REM). We functionally define the boundaries of the REM domain through a combination of in vivo and in vitro assays. We show that an intra-REM domain interaction, mediated by phenylalanine 577, is required to allow interaction of the REM domain with the catalytic core, constraining it in the active conformation.