FDA developed this guidance document to provide clarity to industry and FDA staff about the current review practices for the Humanitarian Device Exemption (HDE) Program. This programmatic guidance addresses commonly asked questions about HDEs and Humanitarian Use Devices (HUDs), including FDA actions on HDE applications, post-approval requirements, and special considerations for devices marketed under the HDE Program. This guidance document reflects changes in the HDE Program resulting from statutory amendments made by the 21st Century Cures Act (Cures Act) and explains the criteria FDA considers to determine if  “probable benefit” has been demonstrated as part of the Agency’s decision-making process regarding marketing authorization for a HUD. This guidance document also reflects amendments made to the HDE provision of the Federal Food, Drug, and Cosmetic Act (FD&C Act) by the FDA Reauthorization Act of 2017 (FDARA).