The genus Orthohantavirus, from the family Hantaviridae and order Bunyavirales, includes 38 recognized species. Species that are pathogenic to humans have a cosmopolitan distribution and are associated with wild and synanthropic rodents. Transmission of orthohantaviruses occurs from rodent hosts to humans due to direct or indirect contact. Disease epidemics are usually correlated with environmental variations, mainly temperature variations and periods of greater rainfall, which increase the dynamics of the rodent population. The lethality of the disease is associated with variants of the virus and can reach 40%. Hemorrhagic fever with renal syndrome (HFRS) usually develops after an incubation period lasting 2–6 weeks, during which subclinical or oligosymptomatic infections are not uncommon. Clinically, it is characterized by the development of sudden fever along with various nonspecific symptoms (e.g., chills, myalgias, nausea). Classically, it can be divided into five clinical phases: febrile, hypotensive, oliguric, diuretic, and convalescent; however, in several cases, these periods may overlap, patients do not always follow a typical clinical course, and, in mild cases, these phases do not even occur. Serology is the most used diagnostic method for detecting Orthohantavirus infection. Infection should be suspected in any patient with acute undifferentiated febrile illness (AUFI) with a marked decrease in platelet count who resides in an endemic area or has recently traveled to an endemic region. To date, no Orthohantavirus infection has an approved specific antiviral treatment, and confirmed and suspected cases need to be treated with supportive measures to maintain the patient’s physiological state. Contact with rodents or their excreta represents the main risk factor for Orthohantavirus infection. Therefore, rodent population represents the most important prevention measure.