Drinking water safety has been primarily dependent on the monitoring of only a limited number of individual chemicals via chemical analysis, which is insufficient to characterize the myriad of hazardous chemicals present in water. Effect-based methods (EBMs) using in vitro bioassays are useful in that they evaluate biological effects from all the known and unknown chemicals in the water and draw on toxicological principles. This thesis aimed to explore the versatility of EBMs for different applications related to drinking water safety. Firstly, we demonstrated how EBMs can be used to compare pilot-scale vs. full-scale treatment processes at a large-scale municipal drinking water treatment plant (DWTP). More importantly, a potentially serious health-relevant effect, genotoxicity, was detected in the raw water as well as finished drinking water from this DWTP. Next, we evaluated the process of artificial infiltration as a treatment method at another municipal drinking water production system. This was in consideration of the fact that water sourced from this type of purification method is prone to contamination with chemical hazards. In addition to these two field studies, we assessed the impact of sample acidification and extract storage time on the outcomes of certain in vitro bioassays, which has been largely under-emphasized when designing sampling strategies for studies using EBMs. For this we collected samples from a wastewater treatment plant that had future water reuse plans for irrigation and potentially as a drinking water source. Our findings revealed that sample acidification did have impacts depending on the selected bioassay(s) and treatment process. Bioactivities in the sample extracts also did not remain unchanged following storage for approximately one year. In the final study, we used EBMs to evaluate two common mycotoxins and their derivatives in the presence of an exogenous metabolic activation system. We chose to study mycotoxins given that their occurrence in surface and drinking waters has been receiving increasing attention. Our findings highlighted that the inclusion of exogenous metabolic activation is useful for detecting the biological effects of mycotoxin metabolites in in vitro bioassays.