Bone marrow stromal antigen 2 (BST-2) is a type II membrane protein with two targeting signals, one of which is located in the cytoplasmic domain and contains a non-canonical dual tyrosine-based motif responsible for its endocytosis from the plasma membrane, and the other is a C-terminal glycosylphosphatidylinositol anchor that facilitates its association with detergent-resistant membranes/lipid rafts and targeting to the apical domain in polarized epithelial cells. Due to its unusual topology at the membrane, BST-2 takes unique and complicated trafficking routes in cells. Recently, a physiological role for BST-2 as the "tetherin" molecule for viruses, especially for HIV-1, has been extensively examined. These studies have shown that the biosynthesis, intracellular trafficking, localization, and structure of human BST-2 are closely related to its antiviral activity. This review provides an overview of the intracellular logistics of human BST-2.