Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death and have extremely poor prognosis. Although, declining trends for some major cancers, death rates are rising in both sexes for pancreatic cancer. Surgical resection is the only curative treatment of pancreatic cancer, but only 10 to 20 percent of patients are candidates for curative surgery. Fifty to sixty percent of patients with pancreatic cancer diagnosed in metastatic stage and 5-year overall survival (OS) rate is less than 5% for metastatic pancreatic cancer. Gemcitabine was the first chemotherapeutic agent that superior to 5-Fluorouracil. In most of the phase II trials combination gemcitabine with cytotoxic chemotherapy or targeted therapy showed promising results, but phase III trials with gemcitabine in combination with cisplatin, oxaliplatin, capacitabine, pemetrexed, irinotecan, bevacizumab, aflibercept, axitinib and cetuximab failed to improve primary endpoint OS. Monotherapy with S-1 demonstrated noninferiority to gemcitabine in OS and S-1 approved for pancreatic cancer in Japan. In a randomized phase II/III ACCORD trial median progression free survival (PFS), response rate (RR), median OS and quality of life were significantly prolonged in FOLFIRINOX arm compared to gemcitabine alone arm. In phase III (MPACT) trial, like FOLFIRINOX regimen, median PFS, RR and OS significantly prolonged with the combination nab-paclitaxel and gemcitabine compared to gemcitabine arm alone. As a targeted agent erlotinib is the first and only agent that demostrate signifiacnt activity with gemcitabine combination in patients with metastatic pancreatic cancer. Gemcitabine plus erlotinib combination significantly prolonged PFS and OS compared to gemcitabine alone arm. Although some combination regimens showed significant OS benefit compared to single-agent gemcitabine, the median OS was less than 1 year. On these grounds, future directions are needed to integrate new targeted agents and combination protocols for metastatic pancreatic cancer.