Solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL) are powerful methods for obtaining peptides and proteins that are otherwise inaccessible. Nonetheless, many peptide sequences are difficult to prepare via SPPS, and cleaved peptides often have low solubility. To address these challenges, we developed a “Synthesis Tag” (SynTag), which effectively improves batch- and flow-SPPS of “difficult sequences”, and simultaneously enhances the solubility of the cleaved peptides. The C-terminal tag provides direct access to native sequences by hydrolysis, or peptide thioesters for NCL. The utility of the tag was demonstrated in the first chemical synthesis of the MYC transactivation domain (143 AA) using a single NCL. We envisage SynTag to become a broadly applicable tool that enables the synthesis and study of previously unattainable peptides and proteins.