Introduction: Our study attempts to characterize mesothelin and GPR30 / estrogen receptor (ER) staining in pancreatic pathology. Materials and Methods: Immunohistochemical staining for mesothelin, GPR30, and ER was performed on a variety of pancreatic lesions. Results: 24 of 42 (57%) adenocarcinomas stained for mesothelin, while 0 of 16 non-carcinomas (0%) stained (p = 0.0000784). 35 of 39 (90%) adenocarcinomas stained for GPR30, while only 4 of 15 (27%) non-carcinomas stained (p = 0.0000036). Apart from stromal staining in one case of mucinous cystic neoplasm, no cases stained for ER. 27 of 37 (73%) adenocarcinoma fine needle aspirates were positive for mesothelin. Discussion: GPR30 is more sensitive, but less specific than mesothelin for pancreatic adenocarcinoma. Mesothelin is detected in most adenocarcinoma fine needle aspirates. ER is rarely detected in pancreatic lesions.