The annual incidence of hepatobiliary cancer has been steadily increasing in the USA from 15,000 in 1993 to 22,200 in 2000. Despite this increase, it still continues to be a rare neoplasm. Surgical resection is the treatment of choice, but a high percentage of patients are unsuitable for resection. These patients have a very poor prognosis because of the lack of efficacious therapy options. Thus, overall survival in these patients ranges from 3 to 12 months, depending on the extent of disease and its site of origin. For some time, mitomycin C, doxorubicin and 5-fluorouracil have been considered among the most active chemotherapeutic agents, with a response rate ranging from 10 to 20%. More recently, gemcitabine has become the reference agent for these neoplasias because of the histologically common origin of biliary cancer and exocrine pancreatic cancer. However, its role has yet to be well-defined. Here we examine clinical trials designed for locally advanced and metastatic biliary tract cancer and review the existing data supporting palliative therapy with gemcitabine alone or in association with other drugs.