Progressive supranuclear palsy (PSP) typically presents with a gradual onset and progressive course of symmetric levodopa-unresponsive parkinsonism characterized by postural instability with falls, supranuclear vertical gaze palsy, dysarthria, dysphagia, and cognitive and behavioral disturbances. Though the clinical course is variable, the typical presentation is usually associated with mortality at 5-9 years after symptom onset. The pathological hallmark of PSP is widespread neuronal cell loss with deposition of aggregated hyperphosphorylated tau, particularly within the midbrain. Etiology remains elusive, but a variable combination of genetic, environmental, oxidative stress, and inflammatory factors may all contribute. Genetic advances have confirmed the H1 tau haplotype on chromosome 17q21.31 to be associated with PSP, while the H2 haplotype seems protective. With greater knowledge of the molecular and genetic aspects of PSP, we can expect future diagnostic and therapeutic challenges to be more effectively met.