High-accuracy quantum chemistry has now been applied for almost 10 years to biological problems involving transition metal active sites. The leading theoretical method is hybrid density functional theory (DFT), usually with the B3LYP functional. The chemical models vary in size, commonly from 30 to 100 atoms treated fully quantum mechanically. Two schools exist, one using the smallest possible adequate models and the other using as large models as possible and sometimes including the entire enzyme by combining quantum mechanics with molecular mechanics. In our group, we have found that the latter approach, which is much more time-consuming and error prone, is seldom needed. In this Account, methods and models will be described and examples of recent applications given. The examples are chosen to illustrate trends and to show cases where theory has predicted new mechanisms not suggested previously.