Control of invasive species is a critical component of conservation biology given the catastrophic damage that they can cause to the ecosystems they invade. This is particularly evident with sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes. Native to the Atlantic Ocean, the sea lamprey's ability to osmoregulate in fresh water, its wide thermal tolerance, generalist diet, and high fecundity allowed it to rapidly reach pest proportions in the prey-rich Great Lakes once it gained access through shipping canals. The invasion exacerbated declines in Great Lakes fisheries caused by overharvest, culminating in the crash of lake trout (Salvelinus namaycush) and other fish populations. In the last 60 years, however, a highly successful sea lamprey control program has reduced sea lamprey to ∼10% of their peak abundance and has been instrumental in enabling the rehabilitation of the Great Lakes ecosystem. In this chapter, we: (1) discuss the likely vectors of the invasion and the physiological attributes of sea lamprey that enabled them to become established in the Great Lakes; (2) review the two cornerstones of the sea lamprey control program—which relies on a combination of pesticides to eradicate multiple generations of larval sea lamprey in their nursey streams, and in-stream barriers to restrict the upstream migration of spawning lamprey—both of which exploit unique physiological vulnerabilities of sea lamprey; (3) describe how sea lamprey control can adversely affect non-target species and how these can be mitigated; (4) show how physiology-based approaches are improving our understanding of the lethal and sublethal effects of sea lamprey on host fishes; and (5) discuss the future of conservation physiology in sea lamprey control. The prime challenge in the next several decades of the Anthropocene will be to further refine the specificity of control tools while maintaining their efficacy, and to adapt to a warming climate and other anthropogenic activities affecting the Great Lakes and their tributaries.