The use of molecular methods in clinical diagnosis has become an essential part of the practice of pathology. In hematopathology, molecular methods are used to identify clonal cell proliferations, chromosomal translocations, the production of abnormal RNA species, somatic mutations of neoplastic cell populations, and quantification of abnormal nucleic acids. Along with the development of new testing methods, molecular pathologists have actively worked to determine the clinical scenarios in which molecular diagnostic testing is indicated and to improve the quality of molecular diagnostic tests. To assure the continued success of nucleic acid–based diagnostics, several key areas warrant attention. This guideline is written for laboratory directors, surgical pathologists, medical technologists, other laboratory personnel, hematopathologists, hematologists, oncologists, and those involved in the promulgation of regulations under which laboratories and manufacturers must operate. This guideline is intended to assist laboratories that rely on nucleic acid–based hematology assay systems to properly implement these techniques, together with the appropriate controls in their laboratories. Furthermore, it is intended to help the laboratorian determine what types of materials and records must be preserved following the laboratory procedure, and for how long. Finally, it is intended to assist those responsible for monitoring compliance with QA programs. This document addresses the following topics as they relate to molecular detection of lymphoid and myeloid clonality, chromosomal translocations, somatic mutations in lymphoid and myeloid neoplasms, and quantification of donor/recipient cell populations after allogeneic transplants, mutations/translocations, and normal RNA species: • Indications for molecular diagnostic testing • Specimen collection, transport, and processing • Assessment of specimen adequacy • Conduct of molecular hematology assays, and sensitivity, specificity, controls, and artifacts • QA • Interpretation of results This document does not address genetic testing for inherited mutations. Refer to CLSI document MM01 for genetic testing guidelines. This document also does not address procedures for validation of molecular diagnostic tests. For information on validation of molecular diagnostic tests, refer to CLSI documents C28, EP05, EP06, EP09, EP12, EP15, EP17, MM01, MM03, and MM06. In addition, this document does not discuss next generation sequencing; therefore, discussion of sequencing or direct sequencing is in reference to Sanger sequencing.