Aquatic invasive species (AIS) are of concern in North America due to their devastating impacts on ecosystems and economies. The Great Lakes region is particularly vulnerable to AIS introduction and establishment with at least 184 nonindigenous species reported in this region from a large number of taxa including viruses, bacteria, diatoms, protozoa, arthropods, mollusks, fish, and plants. Representative species from these groups were explored, describing the features of their natural history and current efforts in prevention and control. Specifically, five AIS that are expected to spread to novel areas in the region are discussed: viral hemorrhagic septicemia virus and heterosporis (pathogens affecting fish), starry stonewort (an alga), zebra mussels (a bivalve), and carps (fishes). Novel strategies for AIS control include next-generation sequencing technologies, gene editing, mathematical modeling, risk assessment, microbiome studies for biological control, and human-dimension studies to address tensions related to AIS management. Currently, AIS research is evolving to adapt to known technologies and develop novel technologies to understand and prevent AIS spread. It was found that AIS control in this region requires a multidisciplinary approach focusing on the life history of the species (e.g., pheromones), adaptive management of anthropogenic structures (e.g., bubble curtains), and the integration of human dimensions to develop efficient management plans that integrate local citizens and management agencies.