Small proteins have historically been under utilized as human therapeutics because they are rapidly metabolized, have short half-lives and can be neutralized by anti-drug immune responses. However, proteins composed entirely of D-amino acids and achiral glycine (D-proteins) are resistant to proteases, which enables them to have longer half-lives and significantly reduced immunogenicity. Consistent with earlier studies by others, we have observed that unconjugated D-proteins fail to elicit an immune response even when repeatedly injected in the presence of a strong adjuvant. This observation has held across several different protein scaffolds injected as monomers or polymers suggesting that the lack of immunogenicity is a general property of D-proteins. This has important broad implications for new design opportunities for therapeutic proteins. Because D-proteins are chemically manufactured new designs can be created which are not possible using biologic manufacturing, including the use of non-natural side chains. Mirror image phage display has been used to create D-proteins that are potent inhibitors of VEGF-A, an important therapeutic target for treating eye diseases and cancers. This presentation will focus on the development of VEGF-A inhibitors as an illustration of the advantages of using D-proteins as therapeutics.