Foldit is a multiplayer online game that allows non-scientists to solve complex protein structure prediction problems. The game uses direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology. Players compete and collaborate to optimize the computed energy of protein structures. Foldit players excel at solving challenging structure refinement problems, particularly those requiring substantial backbone rearrangements to bury hydrophobic residues. Collaborative players develop new strategies and algorithms, exploring not only conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems. Foldit was developed to produce accurate protein structure models through gameplay. Players interactively reshape protein structures to achieve the highest score, which is the negative of the Rosetta energy. The game is designed to be approachable by players with no scientific training, using common terms and highlighting energetically frustrated areas of the protein. Players use intuitive direct manipulation tools, such as pulling on the protein, rotating helices, and rewire beta sheet connectivity. They can also introduce soft constraints and fix degrees of freedom. Available automatic moves are Rosetta optimizations modified for direct protein interaction. Foldit players were able to solve structure prediction problems that were difficult for computational methods. For example, they were able to restructure beta sheets to improve hydrophobic burial and hydrogen bond quality. In one strand swap puzzle, Foldit players were able to get within 1.06 Å of the native structure, while the Rosetta rebuild and refine protocol was unable to get within 2 Å. Foldit players also outperformed Rosetta on five of the puzzles, including cases where they performed significantly better. Foldit gameplay supports both competition and collaboration between players. Players can share structures with their group members and help each other out with strategies and tips. The competition and collaboration create a large social aspect to the game, which alters the aggregate search progress of Foldit and heightens player motivation. Humans use a much more varied range of exploration methods than computers. Different players use different move sequences, both according to the puzzle type and throughout the duration of a puzzle. Within teams, there is often a division of labor; some players specialize in early stage openings, others in middle and end game polishing. Foldit players performed similarly to the Rosetta rebuild and refine protocol for three of the 10 blind puzzles. They outperformed Rosetta on five of the puzzles, including the two above cases where players performed significantly better. A larger set of successful solutions for similar, though non-blind, puzzles are described in the supplementary material. Foldit players were able to distinguish which starting point will be most useful to them. They were able to identify the model closest to the native structure and improve it further. Given the same 10 starting models, the Rosetta rebuild and refine protocol was unable to get as closeFoldit is a multiplayer online game that allows non-scientists to solve complex protein structure prediction problems. The game uses direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology. Players compete and collaborate to optimize the computed energy of protein structures. Foldit players excel at solving challenging structure refinement problems, particularly those requiring substantial backbone rearrangements to bury hydrophobic residues. Collaborative players develop new strategies and algorithms, exploring not only conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems. Foldit was developed to produce accurate protein structure models through gameplay. Players interactively reshape protein structures to achieve the highest score, which is the negative of the Rosetta energy. The game is designed to be approachable by players with no scientific training, using common terms and highlighting energetically frustrated areas of the protein. Players use intuitive direct manipulation tools, such as pulling on the protein, rotating helices, and rewire beta sheet connectivity. They can also introduce soft constraints and fix degrees of freedom. Available automatic moves are Rosetta optimizations modified for direct protein interaction. Foldit players were able to solve structure prediction problems that were difficult for computational methods. For example, they were able to restructure beta sheets to improve hydrophobic burial and hydrogen bond quality. In one strand swap puzzle, Foldit players were able to get within 1.06 Å of the native structure, while the Rosetta rebuild and refine protocol was unable to get within 2 Å. Foldit players also outperformed Rosetta on five of the puzzles, including cases where they performed significantly better. Foldit gameplay supports both competition and collaboration between players. Players can share structures with their group members and help each other out with strategies and tips. The competition and collaboration create a large social aspect to the game, which alters the aggregate search progress of Foldit and heightens player motivation. Humans use a much more varied range of exploration methods than computers. Different players use different move sequences, both according to the puzzle type and throughout the duration of a puzzle. Within teams, there is often a division of labor; some players specialize in early stage openings, others in middle and end game polishing. Foldit players performed similarly to the Rosetta rebuild and refine protocol for three of the 10 blind puzzles. They outperformed Rosetta on five of the puzzles, including the two above cases where players performed significantly better. A larger set of successful solutions for similar, though non-blind, puzzles are described in the supplementary material. Foldit players were able to distinguish which starting point will be most useful to them. They were able to identify the model closest to the native structure and improve it further. Given the same 10 starting models, the Rosetta rebuild and refine protocol was unable to get as close