Cellular gatekeepers are essential to maintain order within a cell and anticipate signals of stress to promote survival. BCL2 associated X, apoptosis regulator (BAX) inhibitor-1 (BI-1), also named transmembrane BAX inhibitor motif containing-6, is a highly conserved endoplasmic reticulum (ER) transmembrane protein. Originally identified as an inhibitor of BAX-induced apoptosis, its pro-survival properties have been expanded to include functions targeted against ER stress, calcium imbalance, reactive oxygen species accumulation, and metabolic dysregulation. Nevertheless, the structural biology and biochemical mechanism of action of BI-1 are still under debate. BI-1 has been implicated in several diseases, including chronic liver disease, diabetes, ischemia/reperfusion injury, neurodegeneration, and cancer. While most studies have demonstrated a beneficial role for BI-1 in the ubiquitous maintenance of cellular homeostasis, its expression in cancer cells seems most often to contribute to tumorigenesis and metastasis. Here, we summarize what is known about BI-1 and encourage future studies on BI-1's contribution to cellular life and death decisions to advocate its potential as a target for drug development and other therapeutic strategies.