Since the current mouse model of DEN infection does not mimic the human disease, studies have been focused towards generating a more suitable murine model of DEN disease. By adapting human and mosquito isolates of DEN into peripheral tissues of mice, novel DEN strains that induce plasma leakage and liver damage in mice have been isolated. Both plasma leakage and liver damage are hallmark features of humans with DHF/DSS. A reverse-genetics system is under development for identifying regulatory elements and structure-function relationships in the viral life cycle. Additionally, efforts will be continued towards isolating new DEN strains that cause a more relevant disease phenotype in mice with primary and sequential DEN infections.