Here, we discuss the role of thioester-containing proteins in innate immune responses of insects. TEPs are represented by multi-member families both in the fruitfly, Drosophila melanogaster, and in the mosquito, Anopheles gambiae. Phylogenetic analysis of the family suggests that in these two dipteran species evolution of TEPs followed independent scenarios as a result of specific adaptation to distinct ecological environments. Research on these two relatively simple model systems, which lack adaptive immunity, may provide new insights into the evolutionary origins and functions of this important protein family.