Progressive supranuclear palsy (PSP) is an atypical parkinsonian disorder that, in spite of its growing recognition, is still underdiagnosed. For management, prognosis, and research, an accurate and early diagnosis is essential. PSP is a relentlessly progressive neurodegenerative disorder, clinically characterized by parkinsonism with prominent axial involvement and postural instability, bulbar symptoms, supranuclear ophthalmoplegia, and executive dysfunction. Abnormal neuronal and glial four-repeat tau aggregations affecting the basal ganglia and selective brainstem structures result in dysfunction of the five frontosubcortical circuits and brainstem functions. Primary therapeutic approaches are based on neurotransmitter replacement and palliative strategies. This article reviews the experience and challenges with neurotransmitter replacement and palliative strategies through an extensive literature search of studies published between 1965 and 2005. The role of and limited experience with alternative therapies, such as deep brain stimulation and pallidotomy, are also discussed. Advances in the development of biological therapies for PSP and a better understanding of its etiopathogenesis will likely result from epidemiologic studies and developed four-repeat tau-transgenic animal models. The management of patients with this disorder poses a considerable challenge and includes symptomatic and palliative strategies, as well as education and support, to improve the quality of life for patients and their caregivers.