Fatigue is the most common symptom in patients with advanced cancer and its prevalence ranges between 50% to 90% overall. In cancer survivors, approximately 30% of patients will experience persistent fatigue for a number of years after treatment. This complex, multidimensional symptom causes disruption in many aspects of quality of life and becomes particularly problematic in the frail and elderly patients. However, cancer-related fatigue is still less investigated and undertreated by the clinicians. Recent guidelines focus on the importance to investigate this distressing symptom at the baseline visit and then at regular intervals. There is no certainty on aetiology and pathogenesis, but it seems that proinflammatory cytokine network is involved both during or after a therapy for cancer. After addressing reversible or treatable contributing risk factors, the treatment can be pharmacologic and non-pharmacologic or combined but it is still largely inadequate especially in case of moderate-severe cancer-related fatigue. Interventions should be tailored to each patient’s specific needs. Finally, cancer-related fatigue has societal and economic costs with increased cancer care.