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The central role that cytochromes P450 play in the metabolism of drugs and other xenobiotics makes these enzymes a major subject for studies of drug disposition, adverse drug effects and drug-drug interactions. Although there has been tremendous success in delineating P450 mechanisms, the concept of the drug-metabolizing ensemble as a functionally integrated system remains undeveloped. However, eukaryotic cells typically possess a multitude of different P450 enzymes that are co-localized in the membrane of endoplasmic reticulum (ER) and interact with each other with the formation of dynamic heteromeric complexes (mixed oligomers). Appreciation of the importance of developing an integral, systems approach to the ensemble of cytochromes P450 as an integral system inspired growing interest of researchers to the molecular organization of microsomal monooxygenase, which remained in the focus of research of academician Archakov for over 40 years. Fundamental studies carried out under his guidance have an important impact on our current concepts in this area. Further exploration of the molecular organization of the system of microsomal monooxygenase as an integral multienzyme and multifunctional system will have an essential impact on our understanding of the key factors that determine the changes in human drug metabolism and other P450-related functions in development, aging, and disease, as well as under influence of drugs, food ingredients, and environmental contaminants.