Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities.