Proliferation of malignant cell also depends on high rate of protein synthesis that increases demands on protein quality control mechanisms. Quality of intracellular proteins are controlled at the level of both endoplasmic reticulum (ER) and 26S proteasome. Disturbances in the functions of either ER or proteasome are associated with particular stress responses. The cellular response to ER stress involves translation inhibition, expression of ER chaperones and degradation of aberrant protein. Elevated expression of HSP70 that binds aberrant proteins or supports their translocation to lysosomes for degradation is the main response to proteasome stress. Both ER and proteasome stress should help the cells to cope with stress conditions but they can also culminate to the cell death.We have examined survival and molecular responses of glioblastoma T98G and neuroblastoma SH-SY5Y cells after ER and proteasome stress.SH-SY5Y cells are more sensitive to proteasome stress, while T98G cells are more sensitive to ER stress. Proteaseome stress increases levels of ubiquitin-conjugated proteins and HSP70 as well as activation of caspase-3 that was attributed to increased expression of pro-apoptotic proteins, PUMA and Noxa, in SH-SH5Y cells. In T98G cells, activation of caspase-3 was associated with increased expression of caspase-4. In both cell lines, the ER stress increases expression of GRP78, the main ER chaperone, and E3 ligase HRD1, involved in retro-translocation of aberrant proteins from ER to cytoplasm for proteasome degradation.Glioblastoma and neuroblastoma cells exhibit different sensitivities and cell responses to both ER and proteasome stress.This work was supported by VEGA 1/0183/23.