The U.S. food supply is characterized increasingly by centralized production and wide distribution of products, and more foodborne disease outbreaks are dispersed over broad geographic areas. Such outbreaks may present as a gradual, diffuse, and initially unapparent increase in sporadic cases. Recognition and reporting by clinicians and local public health officials and the ordering of laboratory tests by clinicians continue to be cornerstones of detecting all outbreaks. New methods--such as active laboratory-based surveillance, automated algorithms for detecting increases in infection rates, and molecular subtyping--facilitate detection of diffuse outbreaks. Routines have evolved for the investigation of multistate outbreaks; they are characterized by rapid communication between local, state, and federal public health officials; timely review of epidemiologic data by expert panels; collaboration on tracebacks with food safety regulatory agencies; and communication with the public and media. Rapid, efficient investigation of multistate outbreaks may result in control of acute public health emergencies, identification and correction of hazardous food production and processing practices, and consequent improvement in food safety.