Background: Armigeres subalbatus is a natural vector of the filarial worm Brugia pahangi, but it rapidly and proficiently kills Brugia malayi microfilariae by melanotic encapsulation. Because B. malayi and B. pahangi are morphologically and biologically similar, the Armigeres-Brugia system serves as a valuable model for studying the resistance mechanisms in mosquito vectors. We have initiated transcriptome profiling studies in Ar. subalbatus to identify molecular components involved in B. malayi refractoriness. Results: These initial studies assessed the transcriptional response of Ar. subalbatus to B. malayi at 1, 3, 6, 12, 24, 48, and 72 hrs after an infective blood feed. In this investigation, we initiated the first holistic study conducted on the anti-filarial worm immune response in order to effectively explore the functional roles of immune-response genes following a natural exposure to the parasite. Studies assessing the transcriptional response revealed the involvement of unknown and conserved unknowns, cytoskeletal and structural components, and stress and immune responsive factors. The data show that the anti-filarial worm immune response by Ar. subalbatus to be a highly complex, tissue-specific process involving varied effector responses working in concert with blood cell-mediated melanization. Conclusion: This initial study provides a foundation and direction for future studies, which will more fully dissect the nature of the anti-filarial worm immune response in this mosquito-parasite system. The study also argues for continued studies with RNA generated from both hemocytes and whole bodies to fully expound the nature of the anti-filarial worm immune response.