Single-agent management of metastatic biliary tract cancers with 5-fluorouracil (5-FU) or gemcitabine has shown limited efficacy, although 5-FU has been shown to be more effective than best supportive care alone. An analysis of phase II trials has suggested that platinums enhanced the efficacy of single-agent fluoropyrimidines. In a phase III randomized trial comparing single-agent gemcitabine with gemcitabine plus cisplatin, the gemcitabine/cisplatin combination significantly improved median overall survival (OS) and progression-free survival (PFS), which established a new option for standard of care. However, the future of cancer medicine lies in newer, targeted agents. In the management of biliary tract cancers, preliminary evidence with epidermal growth factor receptor inhibitors has already demonstrated activity. This article reviews systemic therapies for metastatic biliary tract cancers as they relate to current and emerging standards of care.