In this preprint, Martin-Sancho et al. identify 65 interferon-stimulated genes (ISGs) as cellular host restriction factors against SARS-CoV-2, with 37 of these significantly impairing viral replication. These ISGs include endosomal factors and nucleic acid-binding proteins, which may inhibit viral entry and suppress RNA replication, but the majority of them are ER- or Golgi-resident proteins, which suggests that they impact viral translation, lipid membrane composition and vesicle transport. BST2, which tethers newly synthesized viruses to the plasma membrane and impairs virus release, is identified as a potent restriction factor for SARS-CoV-2 and is found to be counteracted by the accessory protein ORF7a, expression of which rescues virus release. This study draws a comprehensive map of cellular host defence mechanisms against SARS-CoV-2.