With the support of the Scientific Advisory Group for the Origins of Novel Pathogens (SAGO), the World Health Organization (WHO) has published a global framework to help Member States comprehensively investigate the origins of new and re-emerging pathogens. While there are a number of tools available for investigating infectious disease outbreaks, this is the first unified, structured approach to investigating the origins of a novel pathogen. This framework aims to fill that gap by providing a comprehensive set of scientific investigations and studies. It is the first version of a “how-to” guide that will be updated as and when needed, based on feedback from users.