Chemical agents including chlorine and antibiotics are used extensively to control infectious microorganisms. While antibiotics are mainly used to treat bacterial infections, chlorine is widely used for microbial inactivation in the post-secondary disinfection steps of water treatment. The extensive use of these agents has been acknowledged as a driving force for the expansion of antimicrobial resistance (AMR) and has prompted discourse on their roles in the evolution and proliferation of resistant pathogens in the aquatic milieus. We live in a possible “post-antibiotic” era when resistant microbes spread at startling levels with dire predictions relating to a potential lack of effective therapeutic antibacterial drugs. There have been reports of enhancement of resistance among some waterborne pathogens due to chlorination. In this context, it is pertinent to investigate the various factors and mechanisms underlying the emergence and spread of resistance and the possible association between chlorination and AMR. We, therefore, reflect on the specifics of bacterial resistance development, the mechanisms of intrinsic and acquired resistance with emphasis on their environmental and public health implications, the co-selection for antibiotic resistance due to chlorination, biofilm microbiology, and multidrug efflux activity. In-depth knowledge of the molecular basis of resistance development in bacteria will significantly contribute to the more rational utilization of these biocidal agents and aid in filling identified knowledge gap toward curbing resistance expansion.