Pseudo-prolines (Psi Pro) are introduced as a temporary protection technique for serine, threonine and cysteine side chains in standard Fmoc/tBu solid-phase peptide synthesis (SPPS). The incorporation of these novel building blocks into a growing peptide chain proceeds by means of the coupling of preformed, suitably protected Psi Pro dipeptides. For the example of representative model peptides used in protein de novo design, the potential of Psi Pro, to solubilize otherwise sparingly or completely insoluble peptides is demonstrated. Because of their intrinsic propensity for preventing peptide aggregation and beta-sheet formation, pseudo-prolines offer new possibilities for accessing large peptides by convergent strategies and chemoselective ligation techniques.