The precise control of stem cell proliferation is essential to maintain tissue homeostasis. These resident stem cells can adapt their proliferative activity according to tissue demands, allowing normal tissue turnover at homeostasis condition and tissue repair by increasing their proliferation rate under various stress conditions. Although the stress-sensing signaling pathways are shared between stem cells and their differentiated progenies, stress-induced proliferative response is specifically activated in stem cells. The mechanisms underlying this stem cell-specific proliferation control are largely unknown. Here we find that the Sox family transcription factor Sox21a is specifically expressed in progenitor cells in the Drosophila intestine. We show that the stem cell-specific Sox21a expression is necessary for their proliferation both at homeostasis and stress conditions. Interestingly, we demonstrate that Sox21a expression level is induced upon stress exposure, which requires Ras, Jun N-terminal Kinase and Fos. Furthermore, we show that the stress-induced Sox21a expression is sufficient to induce stem cell proliferation. Surprisingly, the Sox21a mutant flies display no obvious developmental defects besides their shortened lifespan, highlighting a role of Sox21a in regulating stem cell proliferation specifically in adult intestine. In summary, our data show that the stem cell-specific Sox21a as an essential proliferation regulator, suggesting that stem cell-specific mechanisms are utilized to generate a unique proliferative response. We are currently investigating how Sox21a interacts with other known stress-sensing signaling pathways, as well as the mechanism(s) controlling stem cell-specific Sox21a expression. In addition, we are trying to identify Sox21a-interacting factors and transcriptional target genes to fully understand the mechanisms by which Sox21a precisely controls stem cell proliferation.