Thioester-containing proteins (TEPs) are conserved proteins among insects that are thought to be involved in innate immunity. In <i>Drosophila</i>, the <i>Tep</i> family is composed of 6 genes named <i>Tep1–Tep6</i>. In this study, we investigated the phylogeny, expression pattern and roles of these genes in the host defense of <i>Drosophila</i>. Protostomian<i> Tep </i>genes are clustered in 3 distinct branches, 1 of which is specific to mosquitoes. Most <i>D. melanogaster Tep</i> genes are expressed in hemocytes, can be induced in the fat body, and are expressed in specific regions of the hypodermis. This expression pattern is consistent with a role in innate immunity. However, we find that TEP1, TEP2, and TEP4 are not strictly required in the body cavity to fight several bacterial and fungal infections. One possibility is that <i>Drosophila</i> TEPs act redundantly or that their absence can be compensated by other components of the immune response. TEPs may thus provide a subtle selective advantage during evolution. Alternatively, they may be required in host defense against specific as yet unidentified natural pathogens of <i>Drosophila</i>.