Expression of the proteome is tightly regulated at the level of protein synthesis. Translational control is a critical homeostatic mechanism that allows the cell to rapidly change its phenotype in the face of an intra- and extra-cellular environment in constant flux. It is becoming increasingly clear that when it comes to protein translation during cell stress, all mRNAs are not treated equally. The translation of the majority of mRNAs is compromised during cell stresses that induce programmed cell death such as hypoxia, or DNA damage. However, cellular messages harbouring Internal Ribosome Entry Site elements (IRES) within their 5′ untranslated regions are insensitive to stress-induced repression of global translation. Instead, these IRES-containing mRNAs use a poorly understood alternative mechanism of translation that allows continued expression of proteins that are required for the cell to recover from a transient stress or to proceed down the path toward apoptotic death. This review will highlight recent literature that suggests why global translation rates are impaired during stress and apoptosis and how these conditions mediate a switch in the mechanism by which pertinent proteins are synthesized. In addition, recent advances towards our understanding of the physiological role and mechanism of IRES-mediated translation in the context of cell stress-induced apoptosis and human disease will be examined.