Immunoglobulin superfamily (IgSF) proteins are known for their ability to specifically recognize and adhere to other molecules, mediating cell-surface reception and pathogen recognition. Mammalian IgSF proteins such as antibodies are among the best characterized molecules of the immune system; in contrast, the involvement of invertebrate IgSF members in immunity has not been broadly studied. Analysis of the predicted Anopheles gambiae transcriptome identified 138 proteins that have at least one immunoglobulin domain. Challenge with Plasmodium, Gram-negative or Gram-positive bacteria resulted in significant regulation of 85 IgSF genes, indicating potential roles for these molecules in infection responses and immunity. Based on sequence and expression data, six infection-responsive with immunoglobulin domain (IRID 1-6) genes were chosen and functionally characterized with regard to their role in innate immunity. Reverse-genetic gene-silencing assays showed IRID3, IRID5 and IRID6 contribute to viability upon bacterial infection while IRID4 and IRID6 are involved in limiting Plasmodium falciparum infection.