The RNA Recognition Motif (RRM) type RNA binding protein Bruno is required for the differentiation of cystoblasts, the committed daughters of germline stem cells in the Drosophila ovary. To understand how Bruno controls cystoblast differentiation, we used a bioinformatics approach to identify potential mRNA targets of Bruno. One such target is the Sex-lethal (Sxl) transcript MS11, which contains four Bruno Response Elements (BREs) in its 3' untranslated region. Electrophoresis mobility shift assays demonstrated that Bruno specifically binds to the BREs of Sxl MS11 mRNA. Tagged transgenic Sxl MS11 cDNA constructs were used to show that Bruno represses the translation of the Sxl MS11 mRNA via the BRE-containing region in the 3'UTR. The lack of either Bruno or the BRE-containing region leads to overexpression of SXL, which in turn causes defects in cystoblast differentiation similar to the Bruno mutant phenotype. Therefore, Sxl MS11 represents a novel target of Bruno-mediated translational repression required for cystoblast differentiation.