About 30,000 Americans develop pancreatic cancer each year and 30,000 die from it. A large number of case-control and cohort studies have shown that there is a clustering of pancreatic cancer in some families and that this clustering occurs more frequently than one would expect by chance (Ghadirian et al., 2002; Tersmette et al., 2001; Coughlin et al., 2000). For example, Tersmette et al. followed over 340 kindreds enrolled in the National Familial Pancreas Tumor Registry (NFPTR) and found an 18-fold increased risk of pancreatic cancer in the kindreds in which at least a pair of first-degree relatives had been diagnosed with pancreatic cancer at the time the kindred enrolled in the NFPTR. More recently, segregation analyses have suggested that this clustering of pancreatic cancer has a genetic basis. In a complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994, and December 31, 1999, nongenetic transmission models (p< 0.0001) were rejected and the most parsimonious models included autosomal dominant inheritance of a rare allele. Approximately 0.5% of the population is estimated to carry this allele. Five genetic syndromes associated with an increased risk of pancreatic cancer have already been identified. These five syndromes are listed in Table 1 and include (1) BRCA2;(2) familial atypical multiple mole melanoma (p16/CDKN2A)(Lynch et al., 2002);(3) Peutz-Jeghers Syndrome, which is characterized by melanocytic macules on the lips and bucal mucosa and numerous hamartomatous polyps of the gastrointestinal tract (Giardiello et al., 2000);(4) hereditary nonpolyposis colorectal syndrome (HNPCC)(Wilentz et al., 2000); and (5) familial pancreatitis (Lowenfels et al., 1997). These five syndromes only account for 020% of the families in which there is an aggregation of pancreatic cancer. The hunt for the gene or genes responsible for the aggregation of pancreatic cancer in the majority of the families is one of the most exciting areas of pancreatic cancer research at the present time.