Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. The first patient with ME/CFS in Japan was identified and described in 1990 by Prof. Teruo Kitani and Dr. Hirohiko Kuratsune of the Research Institute for Microbial Diseases, Osaka University. Since then, a variety of studies have been performed to determine the objective biomarkers of the disease. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there is to date no direct evidence of neuroinflammation in patients with ME/CFS. Our recent positron emission tomography study successfully demonstrated that microglial activation, which is linked to neuroinflammation, occurs in widespread brain areas in patients with ME/CFS, and is associated with the severity of the neuropsychological symptoms. Thus, evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology of the disease, and for developing objective diagnostic criteria and effective medical treatments for ME/CFS. Here, we describe disease-related pathophysiological findings and topics, and discuss the history of the diagnostic and therapeutic attempts based on previous findings in Japan.