Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating condition characterized by a wide range of symptoms that significantly impact all aspects of life. Despite its high prevalence, ME/CFS remains one of the least studied and misunderstood diseases in modern medicine. It lacks standardized diagnostic criteria due to variations in inclusion and exclusion criteria across different guidelines, and there are currently no effective treatments available. The authors propose a new paradigm that integrates the multifactorial origins of ME/CFS into a cohesive model, emphasizing the role of genetic vulnerabilities and environmental triggers, particularly viral infections, in the development of the disease. This model highlights immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances as key pathological responses. The review discusses the complex pathophysiology of ME/CFS, including systemic inflammation, oxidative stress, endothelial dysfunction, and autonomic dysfunction, and outlines the need for a holistic approach to diagnosis, research, and treatment. The authors also highlight the importance of understanding the role of viral triggers, toxin exposure, and genetic predisposition in the development of ME/CFS. The review concludes with a call for further research to better understand the disease and develop effective treatments.Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating condition characterized by a wide range of symptoms that significantly impact all aspects of life. Despite its high prevalence, ME/CFS remains one of the least studied and misunderstood diseases in modern medicine. It lacks standardized diagnostic criteria due to variations in inclusion and exclusion criteria across different guidelines, and there are currently no effective treatments available. The authors propose a new paradigm that integrates the multifactorial origins of ME/CFS into a cohesive model, emphasizing the role of genetic vulnerabilities and environmental triggers, particularly viral infections, in the development of the disease. This model highlights immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances as key pathological responses. The review discusses the complex pathophysiology of ME/CFS, including systemic inflammation, oxidative stress, endothelial dysfunction, and autonomic dysfunction, and outlines the need for a holistic approach to diagnosis, research, and treatment. The authors also highlight the importance of understanding the role of viral triggers, toxin exposure, and genetic predisposition in the development of ME/CFS. The review concludes with a call for further research to better understand the disease and develop effective treatments.