Studies of cell lines and of animal models of pancreatic cancer have raised a number of provocative questions about the nature and origins of human pancreatic cancer and have provided several leads into exciting new approaches for the treatment of this deadly cancer. In addition, clinicians with little or no contact with human pathology have challenged the way that pancreatic pathology is practiced, suggesting that "genetic signals" may be more accurate than today's multimodal approach to diagnoses. In this review, we consider 8 provocative issues in pancreas pathology, with an emphasis on "the evidence derived from man."