Rodent-borne pathogenic hantaviruses cause two severe and often lethal zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Currently, no US FDA-approved therapeutics or vaccines are available for HFRS/HCPS. Infections with hantaviruses are not lytic, and it is currently not known exactly why infections in humans cause disease. A better understanding of how hantaviruses interfere with normal cell functions and activation of innate and adaptive immune responses might provide clues to future development of specific treatment and/or vaccines against hantavirus infection. In this article, the current knowledge regarding immune responses observed in patients, hantavirus interference with cellular proteins and signaling pathways, and possible approaches in the development of therapeutics are discussed.