As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show remarkable levels of promiscuity. In this work, we try to link this promiscuity to the versatility and malleability of the active site at the hand of examples from our own work. Mainly focusing on the flexibility of protein structures and the presence or absence of water molecules, we establish molecular reasons for observed promiscuity, determine the relevant factors to take into account when predicting binding poses and rationalize the role of individual interactions in the process of ligand binding. A high level of active site flexibility does not only allow for the binding of a large variety of substrates and inhibitors, but also appears to be important to facilitate ligand binding and unbinding.