Molecular Modeling applies principles of computational chemistry to the interaction between a drug and its target, generally a protein. Roche has been a pioneer in the application of molecular modeling in pharmaceutical research, being one of the first companies in the field to design and develop algorithms and interfaces to study drug-protein interaction. The knowledge of the conformational and energy factors involved in “fitting the key to the lock,” a common metaphor for drug-target contact, guides the design of new bioactive substances throughout the initial phases of drug discovery, helps generate hypotheses on the mode of action of new potential drugs and to refine selectivity for a desired target. The molecular modeling scientists also invest in developing new, more refined or project-specific algorithms, new interfaces and data visualization tools. The availability of protein structure via X-Ray Crystallography is an important addition to this toolset. Furthermore, a broad variety of computational approaches are utilized to enable rational drug design also in the absence of structural information.