Dysfunction of multiple brain systems in progressive supranuclear palsy (PSP) has complicated attempts to treat the disease. Neurotransmitter replacement strategies targeting the dopaminergic, cholinergic, and serotonergic systems have been unsuccessful. In order to bypass the degenerated cortico-striato-pallidal loop, we administered the adrenergic agonist idazoxan (IDA) to treat PSP in two randomized double-blind, placebo controlled, crossover studies. Approximately one half of patients enrolled in these studies showed statistically significant improvement in balance and manual dexterity while taking IDA compared to placebo. These results suggest that new therapies that target structures outside of the basal ganglia may be useful for symptomatic treatment of PSP. Applying this strategy and developing treatments that arrest or reverse clinical deterioration in PSP will require improved understanding of the process underlying the illness.