The shortcomings of native peptides as pharmaceuticals have been long known: short duration of action, lack of receptor selectivity, lack of oral bioavailability. However medicinal chemistry offers solutions to the first two limitations and oral bioavailability issues have been addressed with novel routes of administration (e.g. intranasal, inhalation) and injectable depot formulations. The principal issue for peptide drugs has been a short duration of action, widely assumed to be due to proteolysis. While proteolysis is a problem for native peptide structures, modification of the peptide structure by acylation, PEGylation, unnatural amino acids or restricted conformation can largely remove this issue. However rapid clearance from the blood into the urine remains an issue for even proteolytically stable molecules. Medicinal chemistry approaches here have been peptide modifications to slow release from the injection site (hydrophobic, hydrophilic, self-associating depots), PEGylation, fatty acid acylation, and the like. Medicinal chemistry approaches used in successful peptide pharmaceuticals using unnatural amino acids to achieve depot formation are highlighted in this review.