Disinfection of water system is an essential strategy to protect human health from pathogens and prevent their regrowth during water distribution, but the reaction of disinfectant agents with organic matter can lead to the formation of disinfection by-products (DBPs). Given their widespread occurrence, potential human health impacts and (eco)toxicity associated with exposure to DBPs are of particular interest due to their potential carcinogenicity and vary non-carcinogenic effects, such as endocrine disruption. Understanding the public health implications of this emerging issue is crucial for societies and decision-makers, supporting more effective water safety plans. Here, we review the recent literature on the effects of DBPs presented in drinking water and treated swimming pools water, focusing particularly in unregulated compounds and the putative underlying mode of action, linking the available data with adverse health outcomes. Overall, the majority of studies highlight the limited knowledge in the understanding of the underlying mode of action of DBPs. Yet, available evidences indicate that different signaling pathways seem to be involved in the adverse outcomes associated with distinct DBPs classes. The main knowledge gaps in this field are also identified, and future research priorities discussed.