The outcome for patients with metastatic pancreatic ductal adenocarcinoma is dismal. In this article, we will review current first-line treatments for metastatic pancreatic adenocarcinoma focusing on phase III randomized studies. Single-agent gemcitabine, the reference treatment since 1995, offers only slight benefit. Numerous trials using gemcitabine in combination with different cytotoxic agents have resulted in no major improvement compared to gemcitabine alone. Only the gemcitabine-erlotinib combination has shown a small, but statistically improvement in survival. In selected patients with good performance status ECOG 0-1, no cardiac ischemia and almost normal bilirubin level, the Folfirinox regimen, when compared to gemcitabine as single agent, was associated with more toxicities, but also with significant increased survival and delay in the degradation of quality of life. So, Folfirinox is a new more toxic and more efficient regimen that may be considered in patients with good performance status.