Neoplasms of the hepatobiliary system include primary tumors, such as hepatocellular carcinoma and cholangiocarcinoma, and secondary lesions from the metastatic spread of a cancer of nonhepatobiliary origin. Surgical excision remains the mainstay of long-term survival for primary tumors whereas secondary lesions can be treated by multiple modalities, including resection, radiotherapy and radiofrequency ablation. However, diagnosis of hepatobiliary neoplasms often occurs late in the disease process. In this article we will focus on the diagnostic approaches and new molecular diagnostics of primary hepatobiliary cancers and we will discuss how these new developments may impact the detection and management of these recalcitrant cancers.