The endoplasmic reticulum (ER), as a processing plant for the folding and posttranslational modification of proteins, is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed 'ER stress', can perturb ER functions, leading to the activation of a complex response known as the unfolded protein response. Here, we investigated the response of hepatocytes derived from young (4-5 months) and aged (24-26 months) rats to two agents, thapsigargin (TG) and tunicamycin (TM), which act via different mechanisms to induce ER stress. Old hepatocytes displayed greater cell death than young cells following treatment with TG or TM, associated with higher expression of the pro-apoptotic gene gadd153 (also known as chop) and enhanced c-Jun N-terminal protein kinase (JNK) activation. Pharmacologic inhibition of JNK decreased the expression of TG-stimulated gadd153 in old cells and reduced their sensitivity to TG-induced cell death. Inhibition of p38, on the other hand, enhanced TG-induced gadd153 expression and JNK activation, and augmented TG-induced cell death. Additional experiments implicated the PERK/eIF-2 alpha signaling pathway as a contributor to the higher Gadd153 expression and JNK activation, and greater sensitivity of old cells to ER stress.