: Cholangiocarcinoma is responsible of 10–15% of liver cancer cases, being second most common primary liver malignancy just behind hepatocellular carcinoma. It comprises a heterogeneous group of tumors (perihilar, distal and intrahepatic carcinoma) with different cellular origins but with certain similarities among them, especially in their molecular pathways and risk factors such as cholangiopathies, metabolic diseases and even liver fluke infestations, all of them involving chronic inflammation. Said factors interact between them to induce genetic mutations, altered immune response and growth factor signaling that are constantly factors within carcinogenesis onset to a well-defined tumor with important clinical manifestations. In addition, cholangiocarcinoma has a silent clinical presentation with overly aggressive nature and refractoriness to chemotherapy. Nevertheless, with the advent of immunotherapy and genomic studies it has been proposed that novel molecular therapies act directly in oncogenic suppression or enhance immune cells activity in the tumoral microenvironment. Therefore, this review focuses on the immunogenetics of cholangiocarcinoma and the role of epigenetics in the current approach in this tumor and future applications in its management.