Zoonotic infections are important sources of human disease; most known emerging infections are zoonotic (e.g., HIV, Ebola virus, severe acute respiratory syndrome, Nipah virus, and enteropathogenic Escherichia coli) and originated as natural infections of other species that acquired opportunities to come in contact with humans. There are also serious infectious diseases classically considered zoonotic, such as influenza, rabies, bubonic plague, brucellosis, and leptospirosis. More recently, it has been recognized that wildlife constitutes a particularly important source of novel zoonoses. With all this microbial movement, surveillance is considered the first line of public health defense. The zoonotic origin of many human and livestock infections argues strongly for the synergistic value of a One Health approach, which provides the capability to identify pathogens crossing into new species and could provide earlier warning of potential epidemics. This article discusses public health surveillance and major recent surveillance initiatives and reviews progress toward implementing a One Health surveillance framework. Networks discussed include global intergovernmental organizations and recent combined efforts of these organizations; Web-based nongovernmental systems (e.g., ProMED, the Program for Monitoring Emerging Diseases); and networks of bilateral or multilateral government programs (e.g., the CDC's Global Disease Detection [GDD] platform; the U.S. Department of Defense's Global Emerging Infections Surveillance and Response System [GEIS]; regional and subregional networks; and the U.S. Agency for International Development's Emerging Pandemic Threats [EPT] program and its surveillance component, PREDICT). Syndromic surveillance also has potential to complement existing systems. New technologies are enabling revolutionary capabilities for global surveillance, but in addition to serious technical needs, both sustainability and data-sharing mechanisms remain challenges.