Over the past 10 years there has been tremendous success in the area of computational protein design. Protein design software has been used to stabilize proteins, solubilize membrane proteins, design intermolecular interactions, and design new protein structures. A key motivation for these studies is that they test our understanding of protein energetics and structure. De novo design of novel structures is a particularly rigorous test because the protein backbone must be designed in addition to the amino acid side chains. A priori it is not guaranteed that the target backbone is even designable. To address this issue, researchers have developed a variety of methods for generating protein-like scaffolds and for optimizing the protein backbone in conjunction with the amino acid sequence. These protocols have been used to design proteins from scratch and to explore sequence space for naturally occurring protein folds.