In trying to distinguish between clinical diagnostic testing and research projects, words “validated” and “regulated” are mentioned most often. Strict regulations govern the space of clinical diagnostics, to certify the clinical and technical validity. It is based on the results of these tests that diagnoses will be established and patients will be treated; thus, the laboratory performing the tests carries a high degree of responsibility. The Centers for Medicare and Medicaid Services (CMS) regulates all laboratory testing performed on humans in the United States through CLIA—the Clinical Laboratory Improvement Amendments (see cms.gov/clia). NGS-based laboratory-developed tests (LDTs) fall under the category of high-complexity testing in CLIA guidelines. In our opinion, the following factors contribute to the clinical acceptance and diagnostic use of NGS-based testing.