The transmembrane glycoprotein CD82 is a member of the tetraspanin protein family and is a metastasis suppressor implicated in biological processes ranging from fusion, adhesion and migration to apoptosis and cell-morphology alterations. Downregulation of CD82 expression is associated with the advanced stages of many human cancers and correlates with the acquisition of metastatic potential. Recent studies suggest that complex mechanisms underlie CD82 loss of function, including altered transcriptional regulation, splice variant production and post-translational protein modifications, and indicate a central role for CD82 in controlling metastasis as a 'molecular facilitator'. The diverse array of functions of CD82, the complexity of the regulation of CD82 and the prospects for targeting CD82 as a therapeutic approach for the treatment of a variety of metastatic cancers are discussed.