E-cadherin is a calcium-dependent cell-cell adhesion molecule with pivotal roles in epithelial cell behavior, tissue formation, and suppression of cancer. As founder member of the cadherin superfamily, it has been extensively investigated. There are several mechanisms that disrupt E-cadherin function in cancer: inactivating somatic and germline mutations, epigenetic silencing by DNA methylation and epithelial to mesenchymal transition-inducing transcription factors, and dysregulated protein processing.