A wide range of drug targets can be effectively modulated by peptides or macrocycles. Unfortunately, application of these larger, beyond rule-of-five (BRo5) molecules is often limited by a lack of cell permeability. We investigated the use of prodrug groups to reversibly transform cell-impermeable macrocycles into less polar derivatives by concealing hydrogen bond donors and charged functional groups. We demonstrated this strategy using PAMPA and Caco2 membrane permeability assays. Using a cyclic peptide model, we developed masking groups for each of the polar, natural amino acid residues (Ser, Gln, Asn, Glu, Asp, Lys and Arg), which impart membrane permeability to the otherwise impermeant parent molecules. Our results highlight the effectiveness of masking groups that introduce a donor-acceptor swap and show that increases to molecular weight are surprisingly useful, particularly where hydrogen bond donors can be eliminated.