Viruses in the genus Hantavirus can cause one of two serious illnesses when transmitted from rodents to humans: hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Of the two diseases, HPS is more severe with an approximate 40% mortality across the Americas. The high rate of mortality could be reduced if effective therapeutics could be discovered for treatment of this illness. Herein we review approaches being explored for the discovery of therapeutics for HPS and how they could be employed in treatment and prevention of disease.