Gemcitabine monotherapy has been the standard of care for patients with metastatic pancreatic cancer for several decades. Despite recent advances in various chemotherapeutic regimens and in the development of targeted therapies, metastatic pancreatic cancer remains highly resistant to chemotherapy. Previous studies of several combination regimens showed minimal or no significant change in overall survival compared with gemcitabine alone. Secreted protein acidic and rich in cysteine (SPARC) overexpression in pancreatic stromal fibroblasts is considered one of the major causes of chemotherapy resistance. The nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) has been found to be superior to other formulations of paclitaxel because of its favorable pharmacokinetic properties. Initial preclinical studies showed its synergistic effect with gemcitabine in pancreatic cancer, in which nab-paclitaxel is sequestered by SPARC to cause stromal depletion and increasing microvasculature, resulting in higher gemcitabine concentration within the tumor. In the recent phase III multinational Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), the combination of gemcitabine and nab-paclitaxel was shown to be superior to gemcitabine monotherapy, with an increase in median survival of 1.8 months. Combination therapy with gemcitabine plus erlotinib, or with gemcitabine plus nab-paclitaxel, or the multidrug regimen of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) can be considered as first-line chemotherapy for patients with metastatic pancreatic cancer. In this review we will discuss details of the recently approved combination of gemcitabine and nab-paclitaxel for first-line treatment of metastatic pancreatic adenocarcinoma and compare it with other therapeutic options.