Methylphenidate is a psychostimulant originally used for the treatment of attention-deficit disorder. Methylphenidate inhibits neuronal neurotransmitter transporters involved in the uptake of dopamine and norepinephrine at the level of the synapse. Inhibition of these transmitter transporters leads to increased concentrations of dopamine and norepinephrine in the synapse, which results in increasing alertness. The stimulant effect of methylphenidate has been used for the treatment of major depression, poststroke depression, cognitive enhancement in patients with brain tumors, neurodegenerative disorders, HIV disease, fatigue, and as a treatment for delirium and sedation associated with opioid use. Other areas where methylphenidate has been evaluated include gait disorders in the elderly individuals and the treatment of apathy in dementia. Analgesic effects have been demonstrated in preclinical models but true analgesic effects remain to be proven in humans. This article reviews the current use of methylphenidate for symptom management with a critical look at the evidence base for its efficacy in the conditions described.