Pancreatic ductal adenocarcinoma (PDAC) remains among the most aggressive malignancies in the United States. Advances in treatments have slowly increased survival rates; however, outcomes remain dismal, largely due to the insidious onset of the disease and lack of screening tests leading to diagnosis at more advanced disease stages. As we better understand the molecular mechanisms that drive PDAC, we can leverage this technology for early detection of new PDAC or recurrences and find more effective methods to track treatment response. Liquid biopsies are increasingly common for the treatment of many malignancies, leveraging better technology to detect scant quantities of circulating tumor cells (CTCs) or byproducts of tumor biology (e.g., exosomes and microRNA [miRNA]) in the blood stream. When combined with existing biomarkers like CA 19-9, there is promising research that improved diagnostic modalities may be available in the future. Furthermore, these technologies are being leveraged to better prognosticate patients with PDAC and potentially monitor treatment responses not captured by cross-sectional imaging, which may allow for real-time changes in therapeutic strategy. This manuscript will review the molecular mechanisms that drive PDAC development and the biomarkers available for diagnosis and prognostication. Much of the data presented is still investigational, though many trials are ongoing to translate these studies for clinical use.