Residential clusters of non-communicable diseases are a source of enduring public concern, and at times, controversy. Many clusters reported to public health agencies by concerned citizens are accompanied by expectations that investigations will uncover a cause of disease. While goals, methods and conclusions of cluster studies are debated in the scientific literature and popular press, investigations of reported residential clusters rarely provide definitive answers about disease etiology. Further, it is inherently difficult to study a cluster for diseases with complex etiology and long latency (e.g., most cancers). Regardless, cluster investigations remain an important function of local, state and federal public health agencies. Challenges limiting the ability of cluster investigations to uncover causes for disease include the need to consider long latency, low statistical power of most analyses, uncertain definitions of cluster boundaries and population of interest, and in- and out-migration. A multi-disciplinary Workshop was held to discuss innovative and/or under-explored approaches to investigate cancer clusters. Several potentially fruitful paths forward are described, including modern methods of reconstructing residential history, improved approaches to analyzing spatial data, improved utilization of electronic data sources, advances using biomarkers of carcinogenesis, novel concepts for grouping cases, investigations of infectious etiology of cancer, and “omics” approaches.