Pancreatic ductal adenocarcinoma, an exocrine tumor, is the most common type of cancer of the pancreas and one of the top five most prominent causes of cancer-associated mortality worldwide. The survival rate for pancreatic cancer is sadly less than 8%. The high fatality rate is partly related to late diagnosis and partly to the aggressive nature of malignant cells that disseminate to nearby tissues at an early stage of the disease, making treatment difficult. Available treatment choices consist of both medical and surgical: removal of the tumor, use of various medications like chemotherapeutic drugs and immunotherapeutic agents, radiation therapy, and targeted drug therapy. Since most patients suffer from advanced cancer at the time of diagnosis, chemotherapy becomes the primary therapeutic option in such cases. Drugs like Gemcitabine, Abraxane, FOLFIRINOX, and newer combination therapies are all effective in management, either curatively or palliatively. However, chemoresistance poses a significant challenge. Several factors, both intrinsic and acquired, are involved in drug resistance. Here, we review the mechanism of action of the first-line chemotherapy drugs in pancreatic cancer and various factors associated with cancer chemoresistance.