Fatigue is one of the most common symptoms in those with systemic lupus erythematosus (SLE), and may impair daily activities, decrease health-related quality of life and lead to employment disability. In SLE, significant fatigue is reported by two-third of patients and rated as severe by one-third. Due to the highly multifactorial nature of fatigue, its assessment and treatment remains a major challenge in SLE. A careful assessment of its determinants is therefore key for an efficient and individualised management in SLE. First, common causes of fatigue unrelated to SLE such as sideropenic anemia, sleep apnea or adrenal failure should be ruled out based on a thorough medical history as well as targeted clinical and laboratory examinations. Then, disease activity and organ damage due to SLE should be assessed. The relationship between fatigue and disease activity remains very controversial in SLE. In those with active disease, remission is the most appropriate therapeutic target and may improve fatigue. Significant damage such as renal or cardiac failure is also associated with high levels of fatigue in SLE, and symptomatic treatment may also improve fatigue levels. In patients with inactive disease and no significant damage, anxiety and depression are common and independent predictors of fatigue. This requires dedicated assessment and care, including psychological counseling and pharmacological intervention if needed. Besides psychological support, lifestyle changes including physical activity should be incorporated in the management of fatigue in SLE.Learning ObjectivesExplain why fatigue is one of the most common symptoms in SLE and highlight the importance of facing this challenging unmet need in SLEDescribe why the common causes of fatigue unrelated to SLE (e.g. sideropenic anemia, sleep apnoea, etc…) should systematically be ruled outDiscuss the controversial relationship between fatigue and disease activity, and explain the importance of minimising the significant damage commonly associated with high levels of fatigue in SLEExplain why anxiety and depression are common in SLE and act as independent predictors of fatigueExplain why lifestyle changes including physical activity should be incorporated in the management of fatigue in SLE