Background: Deisolation of persons infected with SARS-CoV-2, the virus that causes COVID-19, presented a substantial challenge for healthcare workers and policy makers, particularly during the early phases of the pandemic. Data to guide deisolation of SARS-CoV-2-infected patients remain limited, and the risk of transmitting and acquiring infection has changed with the evolution of SARS-CoV-2 variants and population immunity from previous vaccination or infection, or both. Aims: This review examines the evidence to guide the deisolation of SARS-CoV-2-infected inpatients within the hospital setting when clinically improving and also of healthcare workers with COVID-19 prior to returning to work. Methods: A review was performed using relevant search terms in Medline, EMBASE, Google Scholar, and PubMed. Results and Discussion: The evidence is reviewed with regards to the nature of SARS-CoV-2 transmission, the role of testing to guide deisolation, and the impact of SARS-CoV-2-specific immunity. A paradigm and recommendations are proposed to guide deisolation for inpatients and return to work for healthcare workers.