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To circumvent the constraint imposed by the 20 canonical amino acids on the study of protein structure and function, various chemical and biosynthetic methods have been developed to incorporate unnatural amino acids into proteins. Unnatural amino acids now can be genetically encoded in living cells in a manner similar to that of common amino acids, which expands site-directed mutagenesis to diverse novel amino acids. The use of unnatural amino acids grants researchers a multitude of chemical and physical properties that cannot be found in the normal genetic repertoire, which significantly improves their ability to manipulate proteins and protein-involved biologic processes. Changes have been tailored into proteins to accurately dissect the contribution of hydrogen bonding, hydrophobic packing, cation-π interaction, and entropy to protein stability, as well as to precisely examine the structural and functional role of crucial residues. Unnatural amino acids also enable the introduction of new chemical reactivities, biophysical probes, mock posttranslational modifications, photoactive groups, and numerous other functionalities for the modification and regulation of protein activities. These studies not only reveal fundamental information of protein structure and function but also explore new means for generating novel protein properties and controlling biologic events.