An overview is given of the role of E-cadherin in normal epithelia and cancer, how distinct missense mutations in the E-cadherin encoding gene, CDH1, differently disturb E-cadherin expression and function, what are the recommendations and guidelines for the classification and management of CDH1 mutation carriers, and what strategies are available, or being developed, to predict CDH1 variants pathogenicity. This evidence concerns the gene CDH1 and cancer.