The relationship to Rosetta is integral to the D2D Research Goal.

The Rosetta modeling and design software suite includes algorithms for de novo protein design, enzyme design, ligand docking, structure prediction of biological macromolecules and macromolecular complexes, and many more applications. There are many interfaces for Rosetta, including PyRosetta, a Python interface; RosettaScripts, an XML interface; and Foldit, an interactive protein-folding game.

The RosettaCommons is a consortium of over 150 developers from over 25 laboratories around the world, who contribute to and share Rosetta source code.