Tecovirimat (TPOXX®) is an orthopoxvirus-specific antiviral drug developed by SIGA Technologies in conjunction with the US Department of Health and Human Services' Biomedical Advances Research and Development Authority. It acts by inhibiting the activity of the orthopoxvirus VP37 envelope wrapping protein, thereby preventing the formation of egress-competent enveloped virions, which are essential for dissemination of the virus in the host. In July 2018, oral tecovirimat was approved in the USA for the treatment of human smallpox disease caused by variola virus in adults and paediatric patients weighing ≥ 13 kg. Tecovirimat was approved under the US FDA's Animal Rule, in which marketing approval is based on its efficacy in relevant animal models. An intravenous formulation of tecovirimat is undergoing phase I development for the treatment of smallpox infection. This article summarises the milestones in the development of tecovirimat leading to this first approval for the treatment of human smallpox disease in adults and paediatric patients weighing ≥ 13 kg.