Particularly, native chemical ligation has facilitated the synthesis of numerous D-proteins, including enantiomeric venom toxins, growth factors and enzymes, including the 90 kDa split-enzyme D-Pfu. The pursuit of more complex D-proteins is perplexed by their size and posttranslational modification status. Multi-segment, one-pot approaches can improve efficiency, but many recruit unique amino-acid reagents that need to be prepared in the laboratories. Another issue involves the rates of ligation reactions, which can potentially be increased by adopting selenocysteine NCL, and template-directed chemical ligations. Easier access to protected building blocks, and their commercial availability, will greatly improve the possibilities for Dprotein chemical synthesis. Design of synthetic routes to Dproteins can also be assisted by computational approaches, such as the open-source 'Aligator' tool. Perhaps, the ultimate goal for D-polypeptide production is to completely circumvent chemical synthesis, with the entire mirror-image translational machinery (ribosome, rRNA, tRNA, tRNA synthetase, etc) served as a replacement.