Chemical disinfection of drinking water results in the formation of disinfection by-products (DBPs). This paper reviews evidence on the overall toxicity of disinfected water instead of focusing on the effects of individual DBPs. The possible health effects of ingesting DBPs include development of cancer and adverse reproductive/developmental outcomes. Only a few of the 600–700 chlorinated by-products are regulated, accounting for only a small portion of the overall toxicity of DBPs. This review showed that current water quality management, based on complying with standard values set for individual DBPs, is insufficient in responding to overall toxicity from DBP species. Because water suppliers typically focus their water quality management efforts on meeting the defined maximum concentration standards for individual regulated parameters, current water management practices may not adequately focus on effectively reducing overall DBP toxicity. Therefore, we recommend a progressive shift towards preventive and holistic DBP management based on a comprehensive health-based risk assessment that takes into account the overall toxicity and is supported by a validation of the control processes. We also present a prioritized research agenda that will help determine risk assessment and management and facilitate the development of regulations. This includes the development of an index for overall DBP toxicity.