Abnormal distribution, modification and aggregation of TAR DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Rapid advances have been made in our understanding of the physiological function of TDP-43, however, the mechanisms associated with its pathogenesis are poorly known. Interestingly, recent evidence suggests that endoplasmic reticulum (ER) stress is strongly associated with TDP-43 toxicity. For instance, a key finding demonstrated that an ALS linked TDP-43 mutant (TDP-43M337V) induces nuclear depletion of transcription factor X-box Binding Protein 1 spliced (XBP1s) in transgenic rat neurons. The potential impact of XBP1s in TDP-43 proteinopathies makes XBP1 a promising target for Investigation. Here we take advantage our robust drosophila models of TDP-43 toxicity carrying TDP-43 Wild type and mutant TDP-43M337V which produce distinct phenotypes when expressed in the eye. We tested transgenic lines of XBP1 RNAi against these fly models and found that knockdown of XBP1 enhances TDP-43 toxicity in both the models, suggesting a genetic interaction between XBP1 and TDP-43. Interestingly, we saw that overexpression of murine XBP1s (mXBP1s) dramatically suppresses the eye phenotype induced by even mutant TDP-43M337V. The observed rescue of the mutant TDP-43M337V yields exciting results.