Each year, state and local health departments respond to more than 1,000 inquiries about suspected cancer clusters. Three quarters of these reports involve situations that are clearly not clusters and can be resolved by telephone. For the remainder, follow-up is needed, first to confirm the number of persons affected, their age, type of cancer, dates of diagnosis, and other factors, and then to compare cancer incidence in the affected population with background rates in state tumor registries. In approximately 5% to 15% of the reported situations, formal statistical testing confirms that the number of observed cases exceeds the number expected in a specific area, given the age, sex, and size of the affected population. Even in these instances, however, chance remains a plausible explanation for many clusters, and further epidemiologic investigation almost never identifies the underlying cause of disease with confidence. The few exceptions have involved clusters of extremely rare cancers occurring in well-defined occupational or medical settings, generally involving intense and sustained exposure to an unusual chemical, occupation, infection, or drug. This article discusses the resources and scientific tools currently available to investigate cancer clusters. It also provides a framework for understanding cancer clusters and a realistic appraisal of what cluster investigations can and cannot provide in the context of community expectations.