Genes acquired from retroviruses have played key roles in the evolution of eutherians. Retrotransposon Gag-like (RTL) genes, such as Peg10 (Rtl2), Rtl1 (Peg11) and Ldoc1 (Rtl7), are required for placenta formation and maintenance, and endocrine function, but the roles of Rtl6 and Rtl5, are less well understood. Now, Fumitoshi Ishino, Tomoko Kaneko-Ishino and colleagues find that RTL5 and RTL6 are required for an effective innate immune response against new bacterial and viral infections. They observe that both RTL6 and RTL5 are expressed in microglia, the innate immune cells of the brain. They discover that RTL6 is expressed in multiple microglial populations, and RTL5 is enriched in round, TMEM119-positive cells. Upon lipopolysaccharine (LPS) injection, RTL6-positive microglia cluster around the LPS, forming a barrier-like structure, whereas RTL5-positive microglia react mainly to injected dsRNA and non-methylated DNA. The authors challenge the brains of knockout mice with LPS and dsRNA and find that LPS removal is significantly reduced in Rtl6 knockout mice, and dsRNA removal is reduced in Rtl5 knockout mice. Together, these data indicate a role for RTL genes in microglia and demonstrate that RTL5 and RTL6 are involved in mounting an effective innate immune response in mouse brains.