The biosynthesis of proteins containing noncanonical amino acids (ncAAs) provides opportunities for dissecting basic biological processes and engineering proteins with “druglike” features using chemistries not found in the 20 canonical amino acids. This seminar will cover advances in introducing noncanonical amino acids into proteins produced in yeast, and applications of “chemically expanded” proteins in basic biology and drug discovery. The yeast Saccharomyces cerevisiae is a key organism for protein engineering and synthetic biology, but tools for noncanonical amino acid incorporation in this organism are underdeveloped. We have made several advances that greatly expand the tools available in this organism, up to and including genome-wide screens to enable yeast to better accommodate alternative genetic codes. These screens also point to opportunities to investigate the fundamental biology of translation and its connection to other cellular processes. In parallel, we have integrated noncanonical amino acid incorporation technology with the protein engineering tool known as yeast display. This enables high throughput construction and evaluation of “chemically expanded” antibodies with properties that cannot be accessed using conventional antibody engineering. Notably, this includes the introduction of irreversible (covalent) functionalities into antibodies that target a key protein in botulinum neurotoxin responsible for neuronal paralysis. Our advances in generating and evaluating chemically expanded antibodies – and other proteins – have resulted in a platform suitable for the discovery of new classes of reagents, diagnostics, and therapeutics.