Parasites are significant groups for carcinogenesis among which liver flukes, including Opisthorchis viverrini and Clonorchis sinensis, are typical representatives causing cholangiocarcinoma (CCA), the second most common primary hepatic malignancy with dismal prognosis. O. viverrini is prevalent in Southeast Asia, infecting 10 million people while C. sinensis has a wider distribution in East Asia and several Southeast Asian countries, affecting more than 35 million people's health. These two worms have some common characteristics and/or discrepancies in life cycle, genome, and transcriptome. As hot spots in recent years, genome and transcriptome research has extracted numerous novel fluke worm-derived proteins, which are excellent for carcinogenic exploration. However, just a handful of these studies have focused on the metabolic pathway. In this study, the main mechanisms of carcinogenesis of both worms, in terms of mechanical damage, metabolic products and immunopathology, and other possible pathways, will be discussed in detail. This review retrospectively describes the main traits of C. sinensis and O. viverrini, their molecular biology and core carcinogenic mechanisms in a contrast pattern.