Cytochrome P450s (CYPs) are ubiquitously found in all kingdoms of life

playing important role in various biosynthetic pathways as well as degradative pathways; accordingly find applications in a vast variety of areas from organic synthesis and drug metabolite production to modification of biomaterials and bioremediation. Significantly

CYPs catalyze chemically challenging C—H and C—C activation reactions using a reactive high-valent iron-oxo intermediate generated upon dioxygen activation at their heme center

while the other oxygen atom is reduced to the level of water by electrons provided through a reductase partner protein. Self-sufficient CYPs

encoding their heme domain and reductase protein in a single polypeptide

facilitate increased catalytic efficiency and render a less complicated system to work with. The self-sufficient CYP enzyme from CYP102A family (CYP102A1

BM3) is among the earliest and most-investigated model enzymes for mechanistic and structural studies as well as for biotechnological applications. An increasing number of self-sufficient CYPs from the same CYP102 family and from other families have also been reported in last decade. In this review

we introduce chemistry and biology of CYPs

followed by an overview of the characteristics of self-sufficient CYPs and representative reactions. Enzyme engineering efforts leading to novel self-sufficient CYP variants that can catalyze synthetically useful natural and non-natural (nature-mimicking) reactions are highlighted. Lastly

the strategy and efforts that aim to circumvent the challenges for improved thermostability

regio-and enantioselectivity

and total turnover number; associated with practical use of self-sufficient CYPs are reviewed.