The P450 superfamily comprises some of the most powerful and versatile enzymes for the site-selective oxidation of small molecules. One of the main drawbacks for the applications of the P450s in biotechnology is that the majority of these enzymes is multicomponent in nature and requires the presence of suitable redox partners to support their functions. Nevertheless, the discovery of several self-sufficient P450s, namely those from Classes VII and VIII, has served as an inspiration for fusion approaches to generate chimeric P450 systems that are self-sufficient. In this Perspective, we highlight the domain organizations of the Class VII and Class VIII P450 systems, summarize recent case studies in the engineering of catalytically self-sufficient P450s based on these systems, and outline outstanding challenges in the field, along with several emerging technologies as potential solutions.