People afflicted with certain rheumatological auto-immune diseases produce autoantibodies directed against a select group of proteins such as the La auto-antigen. Biochemical studies have revealed La to be a promiscuous RNA-binding protein that appears to play a role in a variety of intracellular activities such as processing and/or transport of RNA polymerase III precursor transcripts and translational regulation from internal ribosome entry sites (IRES). We have previously identified an RNA-binding protein that is a Drosophila melanogaster homolog of La (D-La) and shown that early transcript accumulation throughout the embryo is later refined to be most prevalent in the visceral mesoderm, gut, gonads and salivary glands. Here we report the first in vivo genetic characterization of a La homolog in a multicellular eukaryote. Lethality was observed in homozygous larvae harboring a small chromosomal deletion that removed the D-La gene, which was rescued by an inducible D-La cDNA transgene. This implies that D-La confers essential functions for larval development. In addition, loss of D-La function gives rise to defects in embryonic midgut morphogenesis; one of the midgut defects correlates with loss of Ultrabithorax ( Ubx ) expression along the second midgut constriction. Finally, genetic interactions between chromosomal deficiencies that remove D-La and certain Ubx alleles were demonstrated in adults. Our results support the hypothesis that D-La provides essential functions for proper Drosophila development and imply that the conserved La family of proteins may perform critical developmental functions in higher eukaryotes.