• Use of noncanonical amino acid (ncAAs) in therapeutics requires careful evaluation. • NcAA-mediated strategies enable important routes to precisely defined conjugates. • Viral and cell replication can be controlled using ncAA-dependent protein function. • 'Protein medicinal chemistry' with ncAAs can generate more druglike proteins. • Improved incorporation technologies will further advance therapeutic applications. There is growing evidence that noncanonical amino acids (ncAAs) can be utilized in the creation of biological therapeutics ranging from protein conjugates to cell-based therapies. However, when does genetically encoding ncAAs yield biologics with unique properties compared to other approaches? In this review, we attempt to answer this question in the broader context of therapeutic development, emphasizing advances within the past two years. In several areas, ncAAs add valuable routes to therapeutically relevant entities, but application-specific needs ultimately determine whether ncAA-mediated or alternative solutions are preferred. Looking forward, using ncAAs to perform 'protein medicinal chemistry,' in which atomic-level changes to proteins dramatically enhance therapeutic properties, is a promising emerging area. Further upgrades to the performance of ncAA incorporation technologies will be essential to realizing the full potential of ncAAs in biological therapeutics. [ABSTRACT FROM AUTHOR]