The Foodborne Disease Active Surveillance Network (FoodNet) seeks to determine and to monitor the burden of foodborne diseases in the United States more precisely and to attribute these diseases to specific food vehicles or other exposures. These objectives present statistical and epidemiologic challenges. Estimates of the burden of foodborne diseases should include an estimate of the uncertainty in such calculations. Monitoring the burden of foodborne diseases should account for the expansion of the FoodNet population over time. Attributing foodborne diseases to specific vehicles is facilitated by FoodNet case-control studies of sporadic illness. This article discusses the strengths and limitations of the various studies aimed at addressing these objectives in this supplement. Furthermore, because the FoodNet surveillance areas were not chosen specifically to reflect the demographic composition of the US population, this article also discusses the generalizability of FoodNet results to the US population.