Long COVID, a post-acute sequela of SARS-CoV-2 infection, is a newly recognized chronic condition characterized by medically unexplained symptoms that can cause disability in some individuals. Despite significant progress in understanding its epidemiology, biology, and pathophysiology, there is currently no cure for the tens of millions of people affected. The authors review the current state of knowledge regarding the biology and pathophysiology of long COVID, focusing on how proposed mechanisms explain the syndrome's physiology and provide a rationale for experimental medicine and clinical trials. They emphasize the need for sustained investment by funders and industry to advance research and develop therapeutics. The review covers the epidemiology of long COVID, clinical features, and a conceptual framework for the mechanisms driving the condition. Key mechanisms include the consequences of acute infection, post-acute virus persistence, post-acute inflammation, B cell responses and autoimmunity, and thrombotic events and microclots. The authors highlight the importance of early interventions during acute infection to prevent long COVID and discuss potential therapeutic targets, including antiviral drugs, immunomodulators, and therapies targeting specific pathways involved in inflammation and autoimmunity.Long COVID, a post-acute sequela of SARS-CoV-2 infection, is a newly recognized chronic condition characterized by medically unexplained symptoms that can cause disability in some individuals. Despite significant progress in understanding its epidemiology, biology, and pathophysiology, there is currently no cure for the tens of millions of people affected. The authors review the current state of knowledge regarding the biology and pathophysiology of long COVID, focusing on how proposed mechanisms explain the syndrome's physiology and provide a rationale for experimental medicine and clinical trials. They emphasize the need for sustained investment by funders and industry to advance research and develop therapeutics. The review covers the epidemiology of long COVID, clinical features, and a conceptual framework for the mechanisms driving the condition. Key mechanisms include the consequences of acute infection, post-acute virus persistence, post-acute inflammation, B cell responses and autoimmunity, and thrombotic events and microclots. The authors highlight the importance of early interventions during acute infection to prevent long COVID and discuss potential therapeutic targets, including antiviral drugs, immunomodulators, and therapies targeting specific pathways involved in inflammation and autoimmunity.