This paper describes the mechanism and application of an efficient thia zip cyclization that involves a series of intramolecular rearrangements in a cysteine-rich peptide for the synthesis of large end-to-end cyclic peptides. Key functional groups required in this reaction include an N-alpha-cysteine, a thioester, and at least one internal free thiol in a peptide. The zip reaction is initiated by intramolecular transthioesterification through an internal thiol with the thioester. A thiolactone is formed under ring-chain tautomeric equilibrium that favors ring formation in aqueous buffered solution at pH > 7. Successive ring expansions through thiol-thiolactone exchanges in the direction of the amino terminus lend finally to a large N-alpha-amino thiolactone which then undergoes a spontaneous and irreversible ring contraction through a sequence-independent S to N acyl isomerization to form an end-to-end lactam. The reversible thiolactone exchanges are sequence-dependent and the rate-determining steps are shown by rate studies on model peptides. The assistance of internal thiols in reducing the ring sizes and hence the entropy of the thiolactone exchanges correlates well with cyclization rates. Zip-assisted end-to-end cyclizations forming 93- and 99-atom rings through a series of small thiolactone intermediates were 60-200-fold faster under strongly denaturing conditions such as 8 M urea than the corresponding unassisted lactamization. The thia zip reaction has been applied successfully to the synthesis of a 31-amino acid cyclic peptide, the naturally occurring cyclopsychotride that shows the antimicrobial activity. In addition, the thia zip reaction also enables the synthesis of an engineered cyclic 33-amino acid animal defensin by replacing the end-to-end disulfide with a lactam. which retains the antimicrobial activities of the native open-chain form.