Orthohantaviruses cause emerging infections such as hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome in Eurasia and the Americas, respectively. Humans become infected by inhaling the virus-contaminated aerosols or dust and, in isolated cases, via bites/direct contact with infected rodents. Pathogenic orthohantaviruses such as Hantaan, Dobrava, Seoul, and Puumala are found in countries of the Old World, with the mortality rate ranging from 0.4 to 15%. These viruses continue to cause many infections in Asian and European countries. In recent years, orthohantaviruses have been diagnosed in countries where they were not considered endemic, such as India, Vietnam, Thailand, and some African countries. This chapter will provide a synopsis of orthohantaviruses distribution and genetic diversity in endemic areas in the Old World. We will also describe the data on clinical presentation, treatment and current vaccines for orthohantavirus infections. Additionally, the impact of interventions on the HFRS outbreak during the COVID-19 pandemic is discussed. The information provided in this chapter will help optimize and develop strategies for preventing HFRS, a serious human health threat.