Preoperative diagnosis of pancreatic cysts benefits from integrating the clinical, radiological, and cytological features. As patient management algorithms evolve to increasingly nonsurgical options, accuracy in distinguishing mucinous from nonmucinous and benign from malignant mucinous cysts is important. This review focuses on pseudocysts, serous cystadenomas, intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Patients with pseudocysts almost always present with pancreatitis and are usually medically managed. Radiological studies reveal a unilocular cyst mostly in the pancreatic tail. Cyst fluid is thin, with high amylase but low carcinoembryonic antigen (CEA) levels. DNA mutations are absent. Serous cystadenomas are benign and do not require resection. Patients are usually asymptomatic and have microcystic or macrocystic masses anywhere in the pancreas. Cytology is frequently nondiagnostic. CEA and amylase levels are low. DNA analysis may reveal loss of heterozygosity (LOH) at 3p if associated with Von Hippel-Lindau disease. Neoplastic mucinous cysts are highly variable in their presentation. Most are resected. Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged women and demonstrate a septated cyst without dilatation of the main pancreatic duct. Branch duct IPMNs are more common in the pancreatic head of elderly men. Main duct dilatation correlates with main duct or combined type IPMN. Both types of mucinous cysts produce variable amounts of mucin. Cytologically nonmalignant but atypical epithelial cells, even when scant, are an indication of a high risk for malignancy. High CEA level supports a mucinous cyst, as do KRAS mutation and good quality DNA levels. KRAS mutation and multiple LOH support malignancy. Cancer (Cancer Cytopathol) 2010. © 2009 American Cancer Society.