Intrahepatic cholangiocarcinoma (ICC) is an epithelial cancer arising above the second-order bile ducts, and is characterized by high tendency to postoperative recurrence, unclear benefit of chemotherapy and low long-term survival rates. At present, there is lack of specific markers for early diagnosis of ICC, so it is always diagnosed at a mid-late or late stage. With the in-depth study of the molecular pathogenesis of ICC, some key regulators such as antioncogenes p53 and p16, proto-oncogenes Ras, and miRNA and histone modifications have been found, which may become the therapeutic targets. Here, the authors address the research progress on the molecular profiling of ICC based on the DNA-RNA-protein central dogma.