The initial recognition of hantavirus pulmonary syndrome (HPS) as a new disease associated with a cluster of acute respiratory deaths among American Indians in the southwestern United States in 1993 bears little resemblance to the current understanding of this syndrome. HPS is now recognized as a zoonotic disease that has been endemic throughout the Americas for at least 40 years and that is closely linked to population densities and virus dynamics among a specific subfamily of rodents. The classic disease description has also been markedly broadened to include a spectrum of illness that ranges from asymptomatic infection to fulminate cardiorespiratory failure. Clinical variants with hemorrhagic or prominent renal manifestations have also been recognized. Prevention efforts have been targeted at minimizing peri-domestic contact with rodents and their excreta and improving clinical recognition of infection. This paper describes the pathogenesis underlying the profound cardiorespiratory compromise, person-to-person transmission reported in South America, and viable treatment modalities.