Synthetic approaches to Endothiopeptides where the thioamide group has replaced the normal amide link are discussed and investigated. A range of N-protected dipeptide esters (21) has been thionated exclusively, and in high yield, at the amide carbonyl using Lawesson's reagent (25) giving synthetically useful protected endothiodipeptides (55). Investigation of more conventional peptide methodology and its application to these new systems has been carried out. Deprotection of the N-terminus of the endothiodipeptides (55) gives, after coupling, larger tripeptides with a single thioamide link. Extension of the C-terminus is achieved using the phenyl ester as an active ester group, thus avoiding a deprotection step. In this fashion the protected pentapeptide Z-Tyr (Bzl)-Glyt-Gly-Phe-Leu-OMe (87) has been prepared by two routes and represents a monothionated leucine enkephalin analogue. The fully deprotected pentapeptide (83) has been obtained via an alternative derivative, BOC-Tyr (BOC)-Glyt-Gly-Phe-Leu-OBut (94) in a single step, and may have greater and longer lasting analgesic activity than its normal oxygen counterpart. Approaches to the synthesis of novel endothioaziridine peptides are explored. Milder thionation methods are needed to obtain these systems owing to the nature of the aziridine ring. Several direct thionation methods and indirect methods for incorporation of the thionation functionality are investigated.