A solution to the protein folding problem has eluded researchers for more than 30 years. The stakes are high. Such a solution will make 40,000 more tertiary structures available for immediate study by translating the DNA sequence information in the sequence databases into three-dimensional protein structures. This translation will be indispensable for the analy­ sis of results from the Human Genome Project, de novo protein design, and many other areas of biotechnological research. Finally, an in-depth study of the rules of protein folding should provide vital clues to the protein fold­ ing process. The search for these rules is therefore an important objective for theoretical molecular biology. Both experimental and theoretical ap­ proaches have been used in the search for a solution, with many promising results but no general solution. In recent years, there has been an exponen­ tial increase in the power of computers. This has triggered an incredible outburst of theoretical approaches to solving the protein folding problem ranging from molecular dynamics-based studies of proteins in solution to the actual prediction of protein structures from first principles. This volume attempts to present a concise overview of these advances. Adrian Roitberg and Ron Elber describe the locally enhanced sam­ pling/simulated annealing conformational search algorithm (Chapter 1), which is potentially useful for the rapid conformational search of larger molecular systems.