Secretory and transmembrane proteins traverse the endoplasmic reticulum (ER) and Golgi compartments for final maturation prior to reaching their functional destinations. Members of the p24 protein family, which are transmembrane constituents of ER and Golgi-derived transport vesicles, function in trafficking some secretory proteins in yeast and higher eukaryotes. Yeast p24 mutants have minor secretory defects and induce an ER stress response that likely results from accumulation of proteins in the ER due to disrupted trafficking. We tested the hypothesis that loss of Drosophila melanogaster p24 protein function causes a transcriptional response characteristic of ER stress activation.We performed genome-wide profiling experiments on tissues from Drosophila females with a mutation in the p24 gene logjam (loj) and identified changes in message levels for 641 genes. We found that loj mutants have expression profiles consistent with activation of stress responses. Of particular note is our observation that approximately 20% of the loci up regulated in loj mutants are Drosophila immune-regulated genes (DIRGs), many of which are transcriptional targets of NF-kappaB or JNK signaling pathways.The loj mutant expression profiling data support the hypothesis that loss of p24 function causes a stress response. Genes involved in ameliorating stress, such as those encoding products involved in proteolysis, metabolism and protein folding, are differentially expressed in loj mutants compared to controls. Nearly 20% of the genes with increased message levels in the loj mutant are transcriptional targets of Drosophila NF-kappaB proteins. Activation of NF-kappaB transcription factors is the hallmark of an ER stress response called the ER overload response. Therefore, our data are consistent with the hypothesis that Drosophila p24 mutations induce stress, possibly via activation of ER stress response pathways. Because of the molecular and genetic tools available for Drosophila, the fly will be a useful system for investigating the tissue-specific functions of p24 proteins and for determining the how disrupting these molecules causes stress responses in vivo.