For many years, the ability to predict protein stability or protein function from structure has been considered a major scientific goal with significant practical implications in protein engineering. The Human Genome Project has accelerated the need to achieve that goal. With nearly 100,000 protein-coding genes, fast computer algorithms will be required for structural determination as well as for physical and functional analysis. With more than 10,000 structures already in the protein database, structure alone is clearly not sufficient for a comprehensive understanding of function and regulation. Human intervention in medicine and biotechnology—either by genetic manipulation aimed at introducing specific protein mutations that modify stability or functionality, or by designing new drugs that regulate or modify protein function—requires a clear understanding of the relationships between structure and function. These relationships are mediated by energetics. Proteins are closely packed macromolecules exhibiting a large number of noncovalent atomic interactions that define not only their three-dimensional structure and stability, but also their functional properties. While the relationships between energetics, folding, and stability have been explored by many researchers, the relationships between protein stability and functional cooperativity remain largely unknown. It is well-known that many proteins undergo conformational changes during function or that conformational flexibility is critical to biological activity. These functional properties are dictated by the same interactions that define stability. Thus, functional properties of proteins (e.g., the transmission of binding effects, cooperative interactions, molecular signaling, and allosterism) are defined by energetics, and more precisely by the specific way in which stabilizing interactions are distributed throughout the protein structure. These interactions not only define the overall structure and stability of a protein, but the presence and location of regions with different propensities to undergo conformational rearrangements. Stability and function are linked to each other, and the elucidation of the specific ways in which they are related is a major goal in the postgenomic era.