Pancreatic cancer remains one of the most clinically challenging cancer despite the advancement in molecular characterization of this disease. Malignancy of this disease is characterized by the constitutively activated mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is activated by growth factors, mitogens, hormones, cytokines and environmental factors. Activated MAPK induces expression of downstream genes and regulates cell proliferation, survival, differentiation, motility, receptor signaling, senescence and transport. Activation of MAPK in pancreatic cancer is associated with a poor prognosis and results in limited treatment options. This poor prognosis elicits a need for the development of effective therapeutic measures to treat and improve pancreatic cancer patient survival. MAPK targeted pancreatic cancer therapy has been developed in the last few decades with the use of a number of inhibitors. Inhibitors of RAS, MEK1/2 and ERK1/2 are the main drugs used pre-clinically and in clinical settings of pancreatic cancer treatment. Although these inhibitors have shown some clinical benefits, extensive research on the development of new MAPK signaling pathway inhibitors for the treatment of pancreatic cancer is warranted.