OBJECTIVES: We explore ways to reduce errors in laboratory diagnosis of severe acute respiratory syndrome-coronavirus 2 infection by considering preanalytic, analytic, and postanalytic sources. To address preanalytic challenges, we first consider alternative anatomic sites for specimen collection, then discuss self-collection, alternative sampling devices, and transport media. Strengths and limitations of various analytic test systems are considered in the context of postanalytic challenges associated with making test results meaningful, specifically considering the complex relationship between "positive" test results and reproduction and shedding of intact virus. Finally, we provide recommendations regarding healthcare worker surveillance and release of patients with coronavirus disease 2019 from isolation. DATA SOURCES: Material was derived from a Webinar available to the public, manufacturer's websites, U.S. Food and Drug Administration, and Centers for Disease Control and Prevention websites and from both peer-reviewed papers identified by PubMed search and nonpeer-reviewed papers posted on Biorxiv and Medrxiv. Unpublished data came from the Washington State Department of Health. STUDY SELECTION: We included studies that compared diagnostic performance strategies without introducing bias due to use of an imperfect gold standard. Case series and case reports were included as necessary to illuminate the significance of results. DATA EXTRACTION: Data were extracted manually. DATA SYNTHESIS: Sensitivity, specificity, and CIs were computed from article data using a composite reference standard. Nucleic acid-based tests were assumed to perform at 100% specificity. CONCLUSIONS: Although sputum and bronchoalveolar lavage samples provide the highest diagnostic sensitivity for severe acute respiratory syndrome-coronavirus 2, nasopharyngeal, mid turbinate, and nasal specimens are suitable in most cases and require less use of personal protective equipment. When desired sampling materials are unavailable, alternatives may be substituted with no loss of performance. Both reverse transcriptase polymerase chain reaction tests and rapid nucleic acid-based tests offer good performance in most circumstances. Testing is not required to release most patients from isolation.