Peutz-Jeghers syndrome is clinically characterized by mucocutaneous melanocytic pigmentation, intestinal hamartomatous polyposis and a significantly increased risk of developing cancer. Mutations in the serine/threonine kinase (STK-)11 gene, also designated LKB1, are found in approximately 60% of cases of Peutz-Jeghers syndrome. There is evidence that genetic heterogeneity exists and gene(s) that have not yet been discovered may be responsible for the disease. Since most mutations in Peutz-Jeghers syndrome are null alleles and are dispersed throughout the entire STK11/LKB1 gene, the mutation screening strategies that combine approaches at both the DNA and RNA level are favored. Based upon the identification of novel mutational mechanisms, the impact of RNA-based screening for germinal STK11/LKB1 mutations in Peutz-Jeghers syndrome are specifically discussed.