The presence of xenobiotic compounds in biological wastewater treatment processes with activated sludge may reduce microbial communities, disrupt microbial diversity, and diminish system performance. Shock loads and unusual operating events in these biological systems have negative impacts on their efficiency and reliability for pollutant degradation, thereby posing high risk to microorganisms and water quality of receiving treated water bodies. The severity and characteristics of the occurring damage are determined by the toxic contaminant's degree, nature and mode of application. This review highlights the effects of metabolic uncouplers, heavy metals, carbon nanotubes, pharmaceuticals and personal care products, nanoparticles, and phenolic compounds stress on microbial biomass in activated sludge systems. The synergistic, antagonistic, and shock load toxic effects of hybrid substances exposure in an activated sludge sequential batch reactor (SBR) system on organic and nutrient removal, system efficiency, and toxicants biodegradation are discussed. The findings can be used to provide a theoretical foundation and professional assistance for optimizing the shock impacts of these toxic substances on biological wastewater treatment systems, which will help to reduce their negative effects on treatment system efficiency. © 2022 Wiley-VCH GmbH.