Numerous studies have demonstrated the suitability of cytology specimens for molecular analysis. When combined with the ability to acquire tissue in a minimally invasive manner, testing on cytology specimens is an especially attractive method for further refining diagnosis, determining prognosis, and predicting likely response to therapy as well as monitoring disease. As the demand for testing of small specimens increases, the burden of determining whether a specimen should be referred for testing will increasingly be placed on the pathologist. Although molecular laboratories that perform this testing will also evaluate the suitability of the specimen, familiarity with the criteria for suitability, which includes an understanding of the limitations of the assay methodology, will assist in determining which specimens are appropriate for referral. Selection of specimen(s) for testing should be paired with knowledge of the testing methodology used and its limitations, as well as the tumor enrichment capabilities of the laboratory. In addition to an expanding need to participate in the referral of specimens for testing, the cytopathologist will increasingly serve as a critical link in the communication between molecular laboratory and clinical team. Diagn. Cytopathol. 2012;40:511–524. © 2012 Wiley Periodicals, Inc.