E-cadherin is a well-recognized molecule that is important in cell adhesion. Its abrogation has been linked to increased invasiveness in several malignancies. The normal immunohistochemical localization of E-cadherin is the cell membrane, however, both cytoplasmic and nuclear immunostaining has been reported. Loss of membrane staining and/or nuclear staining for E-cadherin is seen in 100% of cases of solid pseudopapillary tumors (SPTs) of the pancreas. In the context of SPT, E-cadherin staining is of diagnostic use. Nuclear staining has been seen in cases of pancreatic neuroendocrine tumors, Merkel cell carcinomas, clear cell renal cell carcinoma, esophageal squamous carcinoma, colorectal and gastric cancer, and synovial sarcoma. The difference in the staining patterns seen (complete loss vs. nuclear staining) is due to the type of E-cadherin antibody used. Antibodies recognizing the extracellular domain show loss of E-cadherin staining in SPT, whereas the antibody to the cytoplasmic domain results in nuclear staining in all cases of SPT. Therefore, E-cadherin staining is of diagnostic use in the immunohistochemical work-up of SPT. Nuclear E-cadherin staining of pancreatic neuroendocrine tumors identified a subset of cases with more aggressive potential, whereas nuclear staining of clear cell renal cancers identified a subset of tumors with a better prognosis. The exact mechanism by which E-cadherin enters the nucleus is not known but it is likely that it is closely related to several partner molecules such as beta-catenin, p120, and presenilin-1.