Epithelial cadherin (E-cadherin) gene and protein alterations are implicated in the existence of two clearly distinct types of tumors in the stomach (isolated cell and glandular carcinomas), breast (lobular and ductal carcinomas), and thyroid (papillary and follicular carcinomas), as well as in the occurrence of poorly differentiated foci in colorectal and prostate adenocarcinomas. A thorough correlation between clinicopathologic features and molecular data, and the study of early lesions from familial cases provide clues for the understanding of the role played by E-cadherin in these settings.