Cancer-related fatigue is one of the most prevalent and complex symptoms in patients with cancer. Nearly 50% of patients have cancer-related fatigue at the time of diagnosis. This number raises up to 80–96% in patients undergoing chemotherapy and 60–93% in patients receiving radiotherapy. Cancer-related fatigue is often reported as the most distressing symptom associated with cancer and its treatment, thereby having considerable impact on patients’ quality of life and daily functioning. Cancer-related fatigue differs from usual experience of fatigue in healthy individuals with its severity, persistence and it's usually not relieved by rest. Etiology of cancer-related fatigue is multifactorial. There are many treatment-related and disease-related factors that may contribute to the development of cancer related fatigue, many of which are not fully understood. Some of the well investigated contributing factors in cancer-related fatigue are anemia, weight loss, fever, infection, cachexia and depression. This paper will discuss prevalence, size of the problem and currently known pathophysiological mechanisms underlying cancer-related fatigue. There are several hypotheses regarding pathophysiology of cancer-related fatigue such as the pro-inflammatory hypothesis, the serotonin hypothesis, the vagal afferent-activation hypothesis, the anemia hypothesis, and the adenosine triphosphate hypothesis. Understanding specific mechanisms behind cancer-related fatigue could improve diagnosis of cancer-related fatigue and to administration of mechanism-driven interventions and could also provide potential routes for prevention and treatment of cancer-related fatigue.