The majority of emerging infectious diseases originate in animals. Current routine surveillance is focused on known diseases and clinical syndromes, but the increasing likelihood of emerging disease outbreaks shows the critical importance of early detection of unusual illness or circulation of pathogens - prior to human disease manifestation. In this Viewpoint, we focus on one key pillar of preparedness—the need for early warning surveillance at the human, animal, environmental interface. The COVID-19 pandemic has revolutionized the scale of sequencing of pathogen genomes, and the current investments in global genomic surveillance offer great potential for a novel, truly integrated Disease X (with epidemic or pandemic potential) surveillance arm provided we do not make the mistake of developing them solely for the case at hand. Generic tools include metagenomic sequencing as a catch-all technique, rather than detection and sequencing protocols focusing on what we know. Developing agnostic or more targeted metagenomic sequencing to assess unusual disease in humans and animals, combined with random sampling of environmental samples capturing pathogen circulation is technically challenging, but could provide a true early warning system. Rather than rebuilding and reinforcing the pre-existing silo's, a real step forward would be to take the lessons learned and bring in novel essential partnerships in a One Health approach to preparedness.