Experimental evidence for enzymatic mechanisms is often scarce, and in many cases inadvertently biased by the employed methods . Thus, apparently contradictory model mechanisms can result in decade long discussions about the correct interpretation of data and the true theory behind it . However, often such opposing views turn out to be special cases of a more comprehensive and superior concept . Molecular dynamics (MD) and the more advanced molecular mechanical and quantum mechanical approach (QM/MM) provide a relatively consistent framework to treat enzymatic mechanisms, in particular, the activity of proteolytic enzymes . In line with this, computational chemistry based on experimental structures came up with studies on all major protease classes in recent years; examples of aspartic, metallo-, cysteine, serine, and threonine protease mechanisms are well founded on corresponding standards . In addition, experimental evidence from enzyme kinetics, structural research, and various other methods supports the described calculated mechanisms . One step beyond is the application of this information to the design of new and powerful inhibitors of disease-related enzymes, such as the HIV protease . In this overview, a few examples demonstrate the high potential of the QM/MM approach for sophisticated pharmaceutical compound design and supporting functions in the analysis of biomolecular structures.