Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.