Several recent chemical spills have caused large-scale drinking water contamination incidents in Canada and the USA. The study goal was to identify key decisions and actions critical to incident investigations using the 2014 crude MCHM chemical spill in West Virginia USA as a case study. Environmental testing records, scientific reports, government documents, and communication records were reviewed. Results showed that thorough characterization of the spilled liquid and impacted source water is critical to assessing potential public health risks, estimating chemical fate, and designing infrastructure decontamination procedures that can restore infrastructure use. Premise plumbing water testing was not carried-out by responders but testing conducted by other organizations identified the decontamination procedures issued by responders and drinking water screening levels were not adequate to protect public health. Rapid bench-scale tests should be considered to (1) examine water treatment breakdown products, (2) evaluate chemical sorption and leaching by infrastructure materials (i.e., activated carbon, plastics), (3) predict water heater decontamination, and (4) estimate chemical volatilization during fixture use. Key actions to support an effective response and research needs were identified.