Chronic pancreatitis (CP) is an inflammatory, often painful, disease of the exocrine pancreas which leads to exocrine insufficiency. The pathophysiology of pain in CP is incompletely understood. Several hypotheses have been advanced, including pancreatic and extrapancreatic causes. Here, the different pain hypotheses are discussed and evidence is presented that neuroimmune interactions are significant in the pathogenesis of pain generation and inflammation in CP. A better understanding of the complex cellular and molecular mechanisms of neuroimmune interactions should offer possibilities for innovative therapy and long term disease prevention.