Thomas Steitz's scientific career has involved studies of biological structure using X-ray crystallography including developing and refining novel techniques to determine the structure of proteins and nucleic acids with the focus of addressing questions of biological function and mechanism of action. Much of his work has been directed to understanding the structural basis of enzyme mechanisms and on protein-nucleic acid interactions.

His earliest studies on protein structure and mechanism of enzyme action include work on yeast hexokinase demonstrating that substrate binding induces a large conformational change in the enzyme providing experimental support for the induced fit mechanism of enzyme specificity. Subsequently, his work has focused on providing a structural basis for understanding the mechanisms and specificity of gene expression including replication, genetic recombination, transcription, reverse transcription, and translation, the work cited for this award.

He provided the first structure of a DNA polymerase, a bacterial polymerase, followed by studies on mammalian polymerases and the HIV reverse transcriptase. These studies and elucidating structures of recombination enzymes, RNA polymerases, transcription factors, and aminoacyl tRNA synthetases have all provided important and in many cases unexpected insights into biological function in pathways involved in information transfer and genome stability and change. His structural studies on the large ribosomal subunit provided the first atomic level insights into the structure and function of the ribosome, the site of protein synthesis in the cell.

Further studies have refined insights into principles of RNA folding, stability, and RNA-protein interaction, and have also addressed questions of the mechanisms of peptide bond formation and other aspects of protein synthesis on the ribosome. Structures of complexes between the large subunit and antibiotics make possible the structure-based design of new antibiotics potentially active against antibiotic resistant microorganisms.

Tom Steitz is in fact a co-founder and Chairperson of the Scientific Advisory Board of a company involved in the translation of the basic studies of the ribosome to be applied to the development of important health care products, effective antibiotics active against presently antibiotic resistant microorganisms. Likely the most significant outcome of the studies on the ribosome from the Steitz lab is the elucidation of the chemical mechanism of RNA catalyzed peptide bond formation and the key role of RNA in ribosome structure and function; the ribosome is a ribozyme.