Tetherin (BST2/CD317) has emerged as a key host cell defense molecule, inhibiting the release and spread of diverse enveloped virions from infected cells. In this chapter, I review the molecular and cellular basis for tetherin's antiviral activities and the function of virally encoded countermeasures that disrupt its function. I further describe recent advances in our understanding of tetherin's associated role in viral pattern recognition and the evidence for its role in limiting viral pathogenesis in vivo.