Pancreatic cancer is the fourth leading cause of death from cancer. Maximizing therapeutic benefit relies on careful review of inter-individual characteristics. Current and future pharmacogenomics principles may assist in this personal approach and may eventually become widespread. Until then, providers must rely on the available data that might be considered most applicable at the current time. Systemic treatment of unresectable or metastatic pancreatic cancer has been based on gemcitabine and gemcitabine containing combinations for nearly fifteen years. Recently, clinical studies have substantiated two effective combination regimens, FOLFIRINOX, and gemcitabine plus nab-paclitaxel. These regimens have become standard of care for many patients. However, interindividual differences including clinical and physiological parameters can have significant implications for treatment planning. Baseline clinical characteristics such as age, performance status, and comorbidities remain a vital consideration in choosing therapy. Pharmacogenomic data are also shedding new light on the disease management. Genes such as BRCA1/2 and ERCC1 are helping to quantify the risk of developing pancreatic cancer and also guiding treatment in the context of efficacy to platinum agents and PARPi. Genetic polymorphisms in nucleoside transporters such as hCNT3 and hENT1 and the enzymes DCK, CDA, and DCTD can help explain the toxicity and efficacy of gemcitabine. Additionally, DPD and UGT1A1 have been useful in rationalizing adverse effects and managing patients who develop severe toxicity to 5-fluorouracil and irinotecan, respectively. Finally, a number of parameters including sequencing of therapy, dose-limiting toxicities, and other practical considerations can all guide the provider in developing an individual, personalized approach to the systemic treatment of unresectable or metastatic pancreatic cancer.