<p>At first glance, immunology and fatigue do not appear to be closely related terms in medicine. Physicians and patients have individual perspectives on the clinical picture of “fatigue” and its close relative, “chronic fatigue syndrome.” The former is used in the sense of tiredness, weariness, enervation, or exhaustion, whereas the latter is more difficult to define, as the deterioration in the affected person’s condition does not end quickly nor can it be ended quickly; it can also be perpetuated by a&#xa0;wide variety of factors. However, due to the COVID-19 pandemic, many new findings on the connection between an activated immune system and chronic fatigue are now available. This is caused by a&#xa0;tight but altered network between the peripheral and central nervous systems, which is ultimately responsible for the “feeling” of not being able to perform. Chronic systemic inflammation leads to dysregulation of signaling molecules, which are then actively transported to the brain under inflammatory conditions. This immunological activity ultimately results in clinically manifest chronic pain and fatigue symptoms. Inflammatory fatigue is therefore a&#xa0;complex condition that is partly based on the innate immune system but also on the subsequent signaling molecules and abnormal immune responses. It is often not possible to normalize this situation without medication, especially without anti-inflammatory medication. One solution would be structured anti-inflammatory therapy aimed at alleviating the symptoms of fatigue and related diseases.</p>