A significant advance in chemical biology in the past two decades is the development of chemoselective peptide ligation methods for protein synthesis. Many of these methods are characterized by a typical prior capture step followed by intramolecular O(S),N-acyl transfer to form a peptide bond at the ligation junction.To be presented in this talk are two such methods developed in our lab. One is a potentially general aldehyde capture peptide ligation method which does not rely on the participation of a side chain functional group.1 With an N-hydroxyl group anchored on the first peptide bond of the amine ligation partner, this ligation reaction is driven by the formation of a 1,2,5-oxadiazinane ring at the capture step and subsequent O,N-acyl transfer to form a 3° amide bond at the ligation site. De-protection of the six-membered cyclic acetal and cleavage of the N-O bond yields a native peptide product. Examples of ligation reactions with various substrates demonstrate the broad reaction scope of this new ligation method. The other is the thioacid capture ligation method developed in the mid-1990s.2 This method involves a prior capture reaction of the C-ter thioacid of the acyl component by the Npys-activated disulfide on the N-ter Cys of the amine component, which is followed by amide bond formation through S,N-acyl transfer. The unique mechanistic features of thioacid capture ligation give it extremely fast reaction kinetics, making it the most efficient ligation method known to date. We will present our latest results on the application of this method for peptide ligation at very difficult amino acid junctions.