To date, DMF has been considered the only solvent suitable for peptide synthesis. Here we demonstrate the capacity of THF and ACN, which are friendlier solvents than DMF, to yield the product in higher purity than DMF. Using various peptide models, both THF and ACN reduced racemization in solution-phase and solid-phase synthesis when compared with DMF. Moreover, the use of ACN and THF in the solid-phase peptide synthesis of hindered peptides, such as Aib-enkephaline pentapeptide and Aib-ACP decapeptide, in combination with the totally polyethylene glycol ChemMatrix resin, gave a better coupling efficiency than DMF