The prognosis of metastatic pancreatic adenocarcinoma has recently begun to improve. In the last several years, first-line therapy with gemcitabine plus nab-paclitaxel or a regimen of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has boosted the median overall survival (OS) duration to 8.5 months and 11 months, respectively, in patients with metastatic pancreatic cancer, compared with a historic OS of only 6 months prior to 2011. Moreover, sequencing these two regimens improved median OS to an unprecedented 18 months. Notably, as newer agents become available and undergo testing, there is some indication that certain subgroups of patients may benefit dramatically from therapies targeting specific pathways in pancreatic cancer. There have been several attempts to assess the molecular differences in the driving mechanisms of pancreatic cancers, and to link these to specific therapies that could be remarkably effective in selected patients. These molecular analyses-based primarily on assessment of DNA mutations but also incorporating RNA sequencing and, in some cases, protein expression analysis-are beginning to reveal specific subtypes of pancreatic adenocarcinoma. Identification of the appropriate therapy for these subtypes may lead to further improved OS in the relevant patient populations. In this article, we review seminal articles that have evaluated the molecular architecture of pancreatic cancer. We compare the methods used and the molecular subtypes defined, and assess the predominant subgroups in order to better understand which therapies may improve patient outcomes.