Background Pain can be a frequent symptom during the natural history of a patient with pancreatic cancer. An increase in incidence with disease progression and the presence of unbearable pain may preclude a curative resection. Materials and methods Even in those patients with resectable pancreatic cancer, the presence of pain has an impact on prognosis. To date, we do not really know why some patients develop pain. Results Perineural cancer cell invasion is one of the most intriguing characteristics of this neoplasia and may in some cases explain the pain sensation. In addition, so-called "neurogenic inflammation" might also play a role in pain generation in pancreatic cancer, just like in chronic pancreatitis. Conclusion In conclusion, understanding the mechanisms of pain in pancreatic cancer could help patients because what counts is not only 5-year survival but also median survival with good quality of life.