Several rodent-borne orthohantaviruses cause hantavirus disease in humans (i.e., hemorrhagic fever with renal syndrome [HFRS], primarily in Asia and Europe, and hantavirus pulmonary syndrome [HPS] in the Americas). Orthohantaviruses are mainly acquired through the inhalation of infectious respiratory particles from rodent urine or feces. Humans are generally dead-end hosts, but the global distribution of these viruses and rare occurrence of human-to-human transmission of some HPS-causing viruses have led to concern about their potential to bring about large epidemics. Consequently, there is an immediate need for effective vaccines against and therapies for HFRS and HPS. We review immunological memory and adaptive responses to human orthohantavirus infections; enumerate strategies, designs, and outcomes of candidate vaccines; and discuss current trends in vaccinology and their applications to the development of vaccines that could aid in prevention of orthohantavirus infection.