In spite the similar starting time, Merrifield C-N-SPPS quickly outpaced N-C-SPPS, due in great part to challenges of avoiding epimerization in peptide coupling steps. Moreover, linking strategies for amino groups in peptide chemistry have arguably been less well developed than those for the attachment of carboxylic esters. As reviewed on entering the twenty-first century, C-N-SPPS by the Fmoc/t-Bu approach was the most common method for the production of peptides; however, several factors have rendered this approach less desirable including needs to minimize product mass intensity (PMI) and to transition towards environmentally friendly solvents and reagents. As discussed above several innovative methods have emerged for Nto C-direction peptide synthesis. Notably, fears of the "danger of racemization" have been assuaged by the development of various coupling protocols that minimize epimerization including approaches using thioacids, vinyl esters, and transamidation. Such coupling strategies have demonstrated potential for minimizing the protection of side chains. In general, carboxylate protection in Nto C-direction peptide synthesis has typically better atom economy than the carbamate protecting groups used in the Cto N-counterpart. In addition, N-C-SPPS gives effective access to carboxylate precursors for derivatization of the peptide C-terminal. In comparing Cto Nversus Nto C-direction peptide synthesis, the various uses of the former approach in the synthesis of products for academic and industrial purposes cannot be overlooked. For example, the preparation of peptide combinatorial libraries for screening against various biological targets is among the most impressive applications of C-N-SPPS. Although N-C-SPPS has been shown to be effective for making specific peptide targets, innovations with respect to resin anchoring strategies are likely needed to enable combinatorial applications.