Calpains and endoplasmic reticulum (ER) stress have both been implicated in renal cell death following exposure to reactive chemical toxicants (RCTs). Therefore, we explored the link between ER stress, calpain, and cell death in renal cell injury due to model RCTs (iodoacetamide, menadione, tert-butyl hydroperoxide) and ER stress inducers (tunicamycin [TUN], thapsigargin [THAPS]). The calpain inhibitor, PD150606, significantly reduced the RCT and TUN-induced cell death in the renal cell line LLC-PK1, but not death induced by THAPS. ER stress was confirmed by the significant induction of GRP78 following exposure to RCTs and ER stress inducers. While GRP94 induction was observed following RCTs and TUN, it was not statistically significant because of variability. THAPS at 5μM significantly induced GRP94, while 20μM caused a calpain-dependent cleavage of GRP94. Caspase-12 and m-calpain were variably induced and/or cleaved following exposure to all toxicants, supporting activation of these signaling pathways. Inhibition of calpain blocked the induction of GRP78 following exposure to RCTs suggesting that calpain was contributing to the observed ER stress following RCTs. In contrast, calpain inhibition did not block ER stress protein induction following exposure to nontoxic concentrations of TUN or THAPS, indicating that calpain inhibition did not block the ER stress protein induction pathways directly. These studies demonstrate a previously unappreciated link between calpain activation and ER stress–associated cell death in renal cells. While further studies are required to clarify the molecular events involved, these results confirm that calpain activation and the ER are important related players in chemically induced renal cell damage.