Understanding biodegradation processes of anthropogenic organic contaminants in natural and engineered environments including soils, sediments, as well as (waste)water treatment plants is a critical step for designing measures that maintain ecosystem services and sustainable access to food and water under increasing human impact. Contaminant biodegradation routes often involve redox reactions with molecular O 2 as the oxidant. These enzymatic oxygenations of anthropogenic organic contaminants lead to oxygenated products that are amenable as substrates in standard catabolic and biosynthetic pathways. Genomic information suggests that the ability of microbes to transform such contaminants, that is, the biodegradation potential, could even be larger than hypothesized on the basis of known enzymes and their function. However, predicting the occurrence of oxidative biodegradation based on genomic inferences of oxygenase abundances in the environment is particularly difficult. On the one hand, the sequence and kinetics of elementary steps leading to O 2 activation and substrate hydroxylation are often enzyme-specific and therefore preclude generalized predictions of pathways, rates, and extents of biodegradation. On the other hand, the substrate specificity is highly variable, even for structurally related enzymes, and subject to evolutionary pressure. Environmental microbiomes are continuously exposed to a broad variety of organic contaminants that causes microbes to adapt their metabolism to xenobiotic compounds as novel substrates and metagenomic information indeed hints at ongoing sequence mutations. It is hypothesized that the evolution of oxygenases that can transform new contaminants in biodegradation processes is tied to the erroneous handling of activated oxygen and the ensuing release of reactive oxygen species (ROS), a phenomenon referred to as O 2 uncoupling. Reactions with ROS can in fact inactivate proteins. Different ROS-scavenging enzymes and repair systems are therefore in place to mitigate the general oxidative stress associated with metabolic reactions involving O 2 . However, it is so far unclear whether alterations of protein sequences and structures emerge as a consequence of ROS formation in O 2 -activating enzymes and whether this process ultimately results in a reduced O 2 uncoupling as microorganisms adapt to new substrates. For protecting themselves against oxidative damage from ROS, many oxidoreductases can transport potentially damaging oxidizing equivalents away from active sites towards the protein surface through redox-active tyrosine/tryptophan chains. Consistent with this hole hopping process and the notion that cellular reductants would scavenge these oxidation equivalents, reconfiguration of metabolic fluxes has been observed upon ROS release from the oxygenase concomitant with faster turnover of reduction equivalents. Thus, even in the presence of defence mechanisms at the enzyme level, modifications of contaminant-degrading oxygenases that allow for reduced extents of ROS formation would appear (at least) metabolically beneficial to the oxygenase-expressing microorganism. These oxygenases enable access to an additional, potentially broad substrate spectrum of environmental contaminants. Several contaminant-degrading oxygenases are considered promiscuous and their alteration to accept alternative substrates constitutes a competitive advantage for the respective microorganisms. However, it is not known whether an modifications of contaminant-degrading oxygenases as a consequence of exposure to xenobiotic substrates is indeed accompanied by reduced O 2 uncoupling and concomitant decrease of ROS formation.