In this issue of CHEST (see page 1466), Zhu et al1 describe an interesting and informative relationship between a germ-line genotypic characteristic (intronic polymorphism rs430397 in the glucose-regulated protein 78 [GRP78] gene) and outcome in non-small cell lung cancer treated with platinum-based therapy. GRP78 is a heat-shock protein that has long been known to play an important role in the cellular response to endoplasmic reticulum (ER) stress. In the setting of cellular stress due to inadequate nutrients, hypoxia, and other unfavorable conditions in the microenvironment, GRP78 ER-associated activity promotes tumor cell survival. Recent data indicate that GRP78-mediated actions outside of the ER may have an even more prominent effect on tumor progression. GRP78 localized to non-ER cytoplasm and cytoplasmic membranes appears to be associated with many protumorigenic activities. Although some cell-surface GRP78-ligand interactions can induce apoptosis, interactions with T-cadherin, α2-macroglobulin, and Cripto have been demonstrated to induce proliferation and cell survival.2 In addition, cytosolic interaction with p58IPK also promotes cell survival.3 Finally, when GRP78 expression is found on the cell surface of tumor cells, it is generally absent in associated normal tissues, suggesting that therapeutic interventions targeting cell-surface GRP78 hold significant promise.