The liver fluke Opisthorchis viverrini (Ov) is endemic in Southeast Asia where more than 10 million people are estimated to be infected. The infection is associated with several hepatobiliary diseases, including cholangiocarcinoma (CCA). Northeast Thailand is a hotspot for Ov transmission, and, despite extensive public health prevention campaigns led by the government, the prevalence of Ov infection is still high. High infection rates result from cultural and ecological complexities where wet-rice agrarian habitats, centuries-old raw-food culture, and the parasite's complex biology combine to create an ideal transmission arena. Here we review the state of our knowledge regarding the social-ecological determinants underlying Ov transmission. We also describe an integrative research rationale for liver fluke control better aligned with sustainable health development.