HIV-related fatigue continues to be the most common complaint of infected people. No physiological factors have been consistent predictors for fatigue; psychosocial factors, particularly depression, have emerged more consistently in studies. While clinicians would want to rule out common causes of fatigue such as hypothyroidism, hypogonadism, or anemia, there is scant research for most interventions, which makes it difficult to make definitive recommendations for their use. Modafinil has the strongest research evidence to date, with multiple studies finding it effective in relieving fatigue. However, researchers must continue to pursue ways to ameliorate fatigue in HIV infection, given the high financial, personal, and social costs suffered by people experiencing it.