Pancreatic cancer is a malignancy with a very poor prognosis, even when radically resected. In advanced disease chemotherapy has a role in terms of clinical benefit and symptoms palliation, more than survival advantage. Gemcitabine as a single agent is the first-line standard treatment since 1997. Several trials failed to demonstrate a survival advantage of chemotherapy doublets or gemcitabine combined with biological agents versus gemcitabine alone in phase III trials. Erlotinib was the only agent to produce a statistically significant improvement of survival when combined with gemcitabine versus gemcitabine alone. Nevertheless, the clinical application of these literature data remains controversial. However, a meta-analysis showed that combination chemotherapy is superior to gemcitabine alone in terms of survival and clinical benefit in selected subgroups of patients. In unresectable locally advanced disease chemotherapy is active, whereas no high level evidence exists about a possible superiority of chemoradiation. Chemotherapy followed by chemoradiation represents a promising treatment schedule, resulting better than chemotherapy alone in a retrospective analysis. Adjuvant chemotherapy is nowadays a standard treatment, with both 5-FU and gemcitabine resulted superior to observation. Instead adjuvant chemoradiation is not a standard, even though it can be suggested in selected subgroups of patients. In resectable locally advanced disease neoadjuvant therapy is still investigational. Chemoradiation or chemotherapy followed by chemoradiation produced promising results in phase II trials. Possible future gain in terms of survival could come from better neoadjuvant treatments in potentially resectable pancreatic carcinoma. Therefore, this setting should stimulate studies with new drugs and combinations and potential biological predictive factors.