Heartland virus is a newly identified phlebovirus that was first isolated from two northwestern Missouri farmers hospitalized with fever, leukopenia, and thrombocytopenia in 2009. Based on the patients' clinical findings and their reported exposures, the virus was suspected to be transmitted by ticks. After this discovery, CDC worked with state and local partners to define the ecology and modes of transmission of Heartland virus, develop diagnostic assays, and identify additional cases to describe the epidemiology and clinical disease. From this work, it was learned that Heartland virus is found in the Lone Star tick (Amblyomma americanum). Six additional cases of Heartland virus disease were identified during 2012-2013; four of those patients were hospitalized, including one with comorbidities who died.