Essentially all of nature’s catalysts are enzymes and they are fundamental for life, as they control most of the biological processes occurring in living systems. After decades of research on the origin of the enormous catalytic power of enzymes, there is not yet a real understanding of why enzymes are so effective. In fact, the discovery of how enzymes work remains one of the challenges of chemistry at the interface with biology and medicine. Although the chemical mechanisms of many enzyme catalyzed reactions have to some extent been elucidated by biochemical and structural studies, the strategies used by enzymes to achieve enormous rate accelerations are still being debated. Elucidating enzyme structure and mechanism is not only important to fully understand the chemistry of life, but it is crucial to design artificial biomimetic catalysts with catalytic power and selectivity similar or larger than that of natural catalysts.