Dengue virus (DENV) belongs to Flavivirus genus and is transmitted from mosquitoes, mainly Aedes aegypti and Aedes albopictus, to human and back to mosquitoes through mosquito bites. A human with DENV infection can be no symptom or have typical Dengue fever and, in some severe cases, Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS) with 15-50% death rate1, 2. Sensitive small animal models are in urgent need for evaluation of candidate drug and vaccine. We have established a mosquito-based DENV transmission model with DENV-2 clinical isolates. With the strong replication activity, the DENV-2 viruses could be transmitted from Aedes mosquitos to Stat1-/- and AGB6 (deficient in type I and II interferon signaling) mice and caused 100% death rate in AGB6 mice. We further showed that D2Y98P virus can be transmitted from mouse blood to mosquito and establish robust replication in the mosquito. Taken together, we have established a transmission mouse model for DENV pathogenesis research. The DENV transmission model will be useful for the evaluation of candidate drug and vaccine development.