The identification of human predisposition genes to severe forms of infectious diseases is important for understanding the mechanisms of pathogenesis, as well as for the detection of the risk groups. This will allow one to carry out targeted vaccination and preventive therapy. The most common approaches to the genetic risk estimation include conducting association studies, in which the groups of patients and control individuals are compared using both preliminarily selected candidate genes and using genome-wide analysis. To search for genetic variants predisposed to severe forms of infectious diseases, it is expedient to form a control that consists of patients with clinically proven infections with asymptomatic or mild forms of the disease. The examples of the use of these approaches to identify genetic factors that predispose one to severe forms of infections caused by viruses from the Flaviviridae family are considered in the review. At present, a number of genetic markers associated with predisposition to tick-borne encephalitis, West Nile fever, and Dengue fever have already been detected. These associations must be confirmed in independent samples. Genetic variants, for which the association with spontaneous recovery during infection with hepatitis C virus, patient’s reaction on antiviral drugs, and the development of liver fibrosis was established, were also detected. The gene variants with more pronounced phenotypic effects will probably be found during further studies; they can be used in clinical practice as prognostic markers of the course and outcomes of infection with the Flaviviridae, as well as of the response to treatment.