Proteins, like other biomolecules, are composed of chiral building blocks. Ribosomes recruit L-(Levorotatory) amino-acids for catalysis, and hence recombinant proteins are largely refrained in the L-framework. In contrast, incorporation of D-(Dextrorotatory) amino acids into L-polypeptides requires the use of engineered ribosomes, post-translational modification systems (PLPdependent enzyme) or non-ribosomal peptide synthetases (NPRS). At the time of writing, proteins entirely comprised of Damino acids have yet to be found in nature and must be synthesized via chemical routes. Though being more difficult to prepare, D-amino acid proteins that fold into reciprocal chirality possess extraordinary potentials in scientific research, spanning from the creation of mirror-image life and mechanistic investigations to the isolation of ultra-stable binders. In this review, we will describe current research surrounding enantiomeric proteins, including both the challenges and opportunities.