IntroductionSince the outbreak of COVID-19 there has been an unprecedented effort from the scientific community to develop tools to help tackle this crisis. According to the Foundation for Innovative New Diagnostics (FIND; 18 March 2021) there are 1025 commercialized SARS-CoV-2 assays currently available and an additional 98 in development, including 655 immunoassays and 437 molecular assays.1 Early in the pandemic, molecular testing using nucleic acid amplification tests (NAATs) became the pillar of COVID-19 diagnostics. Since then, the development of antigen tests, immunoassays, point-of-care, and centralized options means there are now choices to be made as to how, when, and where to deploy these technologies and many guidelines have been developed, often based on Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) guidance.2-4 However, with the rapid emergence of new technologies and new scientific data, these guidelines are very fluid and subject to change. Furthermore, while NAATs are the most sensitive diagnostic tool for COVID-19 infection,3-5 the global demand for diagnostic testing is still such that the use of labour-intensive, specialist techniques needs to be carefully considered.The aim of this review is to provide an international evaluation of real-world testing needs and to define: settings where the ‘next best’ alternatives to NAATs are appropriate; settings where NAATs may not be the best option; how to manage antigen test results; and how to manage negative NAAT results where there is still a strong clinical suspicion of COVID-19. We will further aim to set out the key considerations for defining a testing strategy. Table 1 demonstrates that each testing strategy provides different information on infection status and has different performance metrics, so the right option for the right setting needs to be carefully assessed. Here we also discuss the common challenges facing clinicians and laboratorians when interpreting and supplying COVID-19 diagnostics and provide insights into what will be needed next.Table 1. A summary of the diagnostic testing methodologies for COVID-19.