Fatigue is the most frequent, complex, multidimensional, and debilitating symptom in patients with advanced medical conditions. In the majority of palliative care patients, the aetiology of fatigue is multifactorial and the most common factors associated with fatigue include anorexia/cachexia, anxiety, depression, shortness of breath, sleep disturbances, anaemia, and inflammation. Routine screening for fatigue is essential for optimal assessment of fatigue and history and investigations should always be individualized. Management should initially aim towards identification and treatment of the reversible/underlying causes; however, if there are no reversible causes identified or if the fatigue is not responsive to specific treatments, symptomatic treatment should be considered. For optimal management the multidimensional components of fatigue should be assessed and future research is needed on the use of non-pharmacological treatment such as physical activity, counselling, and/or pharmacological agents such as a trial of psychostimulants or short course of corticosteroids.