A method will be described that allows one to systematically add new building blocks to the genetic codes of living organisms. Over fifty unnatural amino acids have been genetically encoded in both prokaryotic and eukaryotic organisms in response to both three and four base codons with high efficiency and fidelity. These include photoreactive, redox active and fluorescent amino acids, amino acids with unique chemical reactivity, photocaged and metal ion binding amino acids, and posttranslationally modified amino acids and mimetics. This expanded genetic code may allow the generation of proteins and possibly entire organism with novel properties not restricted by the common twenty amino acids. An overview of this methodology and a number of applications will be described.

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