Disinfectants play an important role in maintaining acceptable health standards by significantly reducing microbial loads as well as reducing, if not eliminating, pathogens. This review focuses on quaternary ammonium compounds (QACs), a widely used class of organic disinfectants. Specifically, it reviews the occurrence, microbial adaptation, and degradation of QACs, focusing on recent reports on the ecology of QAC-degraders, the pathways and mechanisms of microbial adaptation which lead to resistance to QACs, as well as to antibiotics. With the help of culture-dependent and nonculture-dependent tools, as well as advanced analytical techniques, a better understanding of the fate and effect of QACs and their biotransformation products is emerging. Understanding the underlying mechanisms and conditions that result in QAC resistance and biodegradation will be instrumental in the prudent use of existing QAC formulations and foster the development of safer disinfectants. Development and implementation of (bio)technologies for the elimination of QACs from treated wastewater effluents will lessen adverse impacts to both humans and the environment.