Active site water molecules are considered an important component in biological systems. They can affect the binding affinity of a protein-ligand complex by bridging ligand and protein through hydrogen bonds, and can also catalyze several biologically relevant reactions via shuttling proton channels. In cytochrome P450 (CYP450), in particular, the active site water molecules play a crucial role in the catalytic functions and mechanism. In fact, the water molecule starts playing a role from the first step of CYP450 itself where it vacates the sixth coordination place for the substrate binding. In the proceeding steps of the catalytic cycle it also plays a role as a proton donor during the formation of the Cpd 0 and Cpd I. Furthermore, the presence of a water molecule can significantly lower the transition state barrier in CYP450s. With an ever-increasing use of computational chemistry tools to study the mechanism and functions of CYP450, accurate modeling of the water molecules in the CYP450s has become an important challenge for a computational biochemist. In the last four decades, several water models have been proposed