Opisthorchiasis is a neglected tropical disease of major proportion, caused by the carcinogenic, Asian liver fluke, Opisthorchis viverrini. This hepatobiliary disease is known to be associated with malignant cancer (cholangiocarcinoma, CCA) and affects millions of people in Southeast Asia. No vaccine is available, and only one drug (praziquantel) is routinely employed against the parasite. Despite technological advances, little is known about the molecular biology of the fluke itself and the disease complex that it causes in humans. The advent of high-throughput nucleic acid sequencing and bioinformatic technologies is enabling researchers to gain global insights into the molecular pathways and processes in parasites. The principal aims of this chapter are to (1) review molecular research of O. viverrini and opisthorchiasis; (2) provide an account of recent advances in the sequencing and characterization of the genome and transcriptomes of O. viverrini; (3) describe the complex life of this worm in the biliary system of the definitive (human) host and how the fluke interacts with this host and causes disease at the molecular level; (4) discuss the implications of systems biological research and (5) consider how progress in genomics and informatics might enable explorations of O. viverrini and related worms and the discovery of new interventions against opisthorchiasis and CCA.