Proteins are the primary macromolecules through which biological function is mediated. Despite their central importance, synthetic chemists often consider them to be the targets of synthetic small molecules rather than the synthetic targets themselves. The repetitive chemical structure of many biological macromolecules suggests a chemical simplicity, yet in practice these molecules are deceptively difficult to assemble using the traditional organic synthesis toolkit. One of the most significant advances in the assembly of these molecules has been the optimization of Merrifield’s solid phase synthesis to produce highly pure, unprotected segments, followed by highly chemoselective, chemical ligation methods to assemble the segments and facilitate precise late-stage modification. The development of the Native Chemical Ligation / Desulfurization approach for protein synthesis will be discussed and how it can be applied to the synthesis of complex macromolecular targets. In addition, a variety of non-native ligation chemistries have been explored through careful optimization of reaction rates top optimize utility and chemoselectivity. Reversible Absorption to a Solid Support (RASS) approach will be presented with applications to protein and nucleic acid targets including DNA encoded libraries. Together, these methods provide a robust toolkit for macromolecule synthesis that has been broadly utilized to advance peptide and protein science.