Long COVID is a debilitating condition affecting at least 10% of individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, with over 65 million cases worldwide. The illness impacts multiple organ systems and can persist for years, often leading to long-term disabilities. Biomedical research has identified various pathophysiological changes and risk factors, and similarities with other viral-onset illnesses like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS) have advanced understanding. Key findings include immune dysregulation, autoantibody elevation, viral persistence, and organ damage. However, current diagnostic and treatment options are insufficient, and clinical trials are needed to address leading hypotheses. Future studies should account for biases, improve testing methods, build on viral-onset research, and engage marginalized populations and patients throughout the research process. The review highlights the need for comprehensive research agendas, improved diagnostics, and effective treatments to manage long COVID effectively.Long COVID is a debilitating condition affecting at least 10% of individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, with over 65 million cases worldwide. The illness impacts multiple organ systems and can persist for years, often leading to long-term disabilities. Biomedical research has identified various pathophysiological changes and risk factors, and similarities with other viral-onset illnesses like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS) have advanced understanding. Key findings include immune dysregulation, autoantibody elevation, viral persistence, and organ damage. However, current diagnostic and treatment options are insufficient, and clinical trials are needed to address leading hypotheses. Future studies should account for biases, improve testing methods, build on viral-onset research, and engage marginalized populations and patients throughout the research process. The review highlights the need for comprehensive research agendas, improved diagnostics, and effective treatments to manage long COVID effectively.