The past 30 years have exposed the global public health and economic threats posed by the emergence of infectious pathogens with epidemic and pandemic potential. Severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS), influenza, Ebola, Marburg, Lassa, Nipah, Zika, and now SARS coronavirus 2 (SARS-CoV-2) each have been the "Disease X" of their time. The risk of future emergence is driven by multiple forces, including climate change, ecosystem changes, and increasing urbanization. The next Disease X could appear at any time, and the world needs to be better prepared.