Cholangiocarcinomas (CCAs) are heterogeneous biliary tract tumors with dismal prognosis. Perihilar CCA (pCCA) involves the large bile ducts of the hepatic hilum, and is the most common type of CCA. Primary sclerosing cholangitis (PSC) is an established risk factor for pCCA. Although the diagnosis of pCCA is challenging, recent advances have been made including cytologic techniques such as fluorescence in situ hybridization. Endoscopic ultrasound with sampling of regional lymph nodes is emerging as a valuable diagnostic modality in the diagnosis and staging of pCCA. Curative treatment options are limited to early stage disease, and include surgical resection and liver transplantation after neoadjuvant therapy. This underscores the importance of early detection, and the need for development of innovative diagnostic tools such as biomarkers. A dense desmoplastic tumor stroma plays an integral role in pCCA progression. The tumor stroma represents an additional target for development of new therapies. Herein, we discuss these advances in the diagnosis and treatment of pCCA.