Our progress in understanding the biology of chronic pancreatitis has been slow, particularly with respect to the pathogenesis of pain, the cardinal symptom. Although traditional theories have focused on anatomic changes, with interstitial and ductal hypertension as the main inciting factors for pain generation, subsequent studies have not confirmed a correlation between ductal pressure and the severity of pain or its relief after ductal decompression. Empirical approaches directed at anatomic causes are at best of marginal value. Although these phenomena are clearly associated with the disease, they are not likely the root cause of the pain. Instead, they probably are inciting factors on a background of neuronal sensitization induced by damage to the perineurium and subsequent exposure of the nerves to mediators and products of inflammation. In this review, we discuss the inherent limitations in our current therapies and try to identify new targets and approaches for the future, such as TRPV1, nerve growth factor-TrkA signaling, and perhaps protease activator receptor-2.