The Great Lakes Fish Monitoring and Surveillance Program (GLFMSP) has served to protect the Laurentian Great Lakes of North America for decades. Top predator fish from each lake are employed as bioindicators of chemical stressors within each lake. While a vast database has been created for legacy contaminants, such as polychlorinated biphenyls and organochlorine pesticides, a recent programmatic shift has transformed GLFMSP into a more proactive new chemical discovery/screening endeavour to capture the burden of more contemporary chemicals in the environment. The transition prompted the need for advanced instrumentation and the evaluation of mass spectrometric approaches beyond traditional electron capture detection and unit mass resolution mass spectrometers. Here the advances in detection methods are documented and the current direction of the program in creating a living database of anthropogenic chemicals affecting Great Lakes fish is highlighted.