The "protein folding problem" consists of three closely related puzzles: (a) What is the folding code? (b) What is the folding mechanism? (c) Can we predict the native structure of a protein from its amino acid sequence? Recent years have seen significant progress in these areas. Foldable proteins and nonbiological polymers are now being designed routinely and are moving towards successful applications. Small protein structures are often well predicted by computer methods, and there is now a testable explanation for how proteins can fold so quickly: A protein solves its large global optimization problem as a series of smaller local optimization problems, growing and assembling the native structure from peptide fragments, local structures first. The folding code is primarily driven by hydrophobic interactions, which are crucial for protein stability and secondary structure formation. The folding process involves a dominant component, with hydrophobic interactions playing a major role. The folding mechanism is described by funnel-shaped energy landscapes, where proteins search for their native states through a series of smaller, more stable structures. The zipping and assembly (ZA) hypothesis suggests that proteins fold by piecing together small, metastable structures, which then grow and assemble into larger, more stable structures. Experimental and theoretical methods have advanced significantly, including fast laser temperature-jump methods, φ-value experiments, single-molecule techniques, and computer simulations using physics-based models. These advancements have led to better understanding of folding kinetics and the development of more accurate structure prediction methods. Physics-based modeling is becoming useful for structure prediction and studying folding routes, with notable successes in folding small proteins and peptides. In conclusion, the protein folding problem has seen substantial progress, and current knowledge is sufficient to guide the design of new proteins and foldamers. The ZA hypothesis provides a viable explanation for how proteins can fold quickly and efficiently.The "protein folding problem" consists of three closely related puzzles: (a) What is the folding code? (b) What is the folding mechanism? (c) Can we predict the native structure of a protein from its amino acid sequence? Recent years have seen significant progress in these areas. Foldable proteins and nonbiological polymers are now being designed routinely and are moving towards successful applications. Small protein structures are often well predicted by computer methods, and there is now a testable explanation for how proteins can fold so quickly: A protein solves its large global optimization problem as a series of smaller local optimization problems, growing and assembling the native structure from peptide fragments, local structures first. The folding code is primarily driven by hydrophobic interactions, which are crucial for protein stability and secondary structure formation. The folding process involves a dominant component, with hydrophobic interactions playing a major role. The folding mechanism is described by funnel-shaped energy landscapes, where proteins search for their native states through a series of smaller, more stable structures. The zipping and assembly (ZA) hypothesis suggests that proteins fold by piecing together small, metastable structures, which then grow and assemble into larger, more stable structures. Experimental and theoretical methods have advanced significantly, including fast laser temperature-jump methods, φ-value experiments, single-molecule techniques, and computer simulations using physics-based models. These advancements have led to better understanding of folding kinetics and the development of more accurate structure prediction methods. Physics-based modeling is becoming useful for structure prediction and studying folding routes, with notable successes in folding small proteins and peptides. In conclusion, the protein folding problem has seen substantial progress, and current knowledge is sufficient to guide the design of new proteins and foldamers. The ZA hypothesis provides a viable explanation for how proteins can fold quickly and efficiently.