Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous biliary malignancy characterized by challenges in early diagnosis, limited efficacy of traditional chemotherapy, and poor prognosis. Due to its significant heterogeneity at the genomic, epigenetic, and molecular levels, molecular testing and targeted therapy have become increasingly important in CCA management, forming an integral part of the era of precision oncology. The development of next-generation sequencing (NGS) has advanced research into the molecular subtypes and therapeutic targets of CCA, including FGFR2 fusions/rearrangements, IDH1 mutations, and BRAF mutations. Recently, two phase III clinical trials, TOPAZ-1 and KEYNOTE-966, have established the pivotal role of immunotherapy combined with chemotherapy in advanced CCA. While precision diagnosis and treatment in CCA have shown promising progress, this field remains in its exploratory phase and faces numerous challenges. This review summarizes recent advancements in the diagnosis, molecular targeted therapy, immunotherapy, resistance mechanisms, and the development of novel strategies for CCA.