Dengue virus (DENV) outbreaks can occur when new DENV strains emerge and replace endemic strains, as during a 1994 epidemic when a foreign dominant (PR-2B) replaced the endemic (PR-1) viral clade. To understand the changes that resulted in the increased fitness of PR-2B, Manokaran et al. compared the two viral sequences and identified mutations that resulted in the increased production of subgenomic flavivirus non-coding RNAs (sfRNAs) by the PR-2B strain. These PR-2B sfRNAs were capable of binding to host TRIM25 and prevented its deubiquitylation, which is crucial for activation of RIG-I, a cytosolic sensor that recognizes viral nucleic acids and induces the expression of antiviral type I interferons by infected cells. These data demonstrate that DENV sfRNAs can bind to host proteins to promote viral evasion of innate immunity and increase viral fitness.