The tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) is a tightly regulated enzyme responsible for dephosphorylating the progrowth lipid messenger molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the plasma membrane. The carboxy-terminal tail (CTT) of PTEN is key for regulation of the enzyme. When phosphorylated, the unstructured CTT interacts with the phosphatase-C2 superdomain to inactivate the enzyme by preventing membrane association. PTEN mutations associated with cancer also inactivate the enzyme. Alternate translation-initiation sites generate extended isoforms of PTEN, such as PTEN-L that has multiple roles in cells. The extended amino-terminal region bears a signal sequence and a polyarginine sequence to facilitate exit from and entry into cells, respectively, and a membrane-binding helix that activates the enzyme. This amino-terminal region also facilitates mitochondrial and nucleolar localization. This review explores PTEN structure and its impact on localization and regulation.