Most patients with pancreatic cancer either present with or eventually develop metastatic disease during the course of their illness. For such individuals, systemic therapy, namely, cytotoxic therapy, represents the mainstay of treatment and is administered with noncurative intent. Of the various chemotherapy options now available for treating metastatic pancreatic cancer, 2 combination regimens, FOLFIRINOX (infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the doublet of gemcitabine and albumin-bound paclitaxel, have emerged as frontline standards of care, based on phase III studies demonstrating a significant survival benefit compared with single-agent gemcitabine. More patients are also now able to be sequenced through 2 or more lines of treatment, with newer regimens such as nanoliposomal irinotecan plus infusional 5-fluorouracil and leucovorin receiving US Food and Drug Administration approval specifically for use in this second-line setting. Selection of therapies remains primarily guided by clinical considerations, particularly performance status, as well as age, comorbid medical conditions, and organ and bone marrow function. In contrast, molecular predictors of efficacy and toxicity have not yet been validated in this disease context. Areas of novel therapeutic development include targeting the stromal microenvironment, exploring combinations of immunotherapeutic agents, and identifying molecular subsets of metastatic pancreatic cancer that may uniquely susceptible to specific strategies, such as hampering DNA damage repair.