Recent studies suggest that genotoxic and non-genotoxic stresses appear to invoke translational checkpoints in order to inhibit protein synthesis. Depending on the stress and/or cell type, this downregulation of protein synthesis may either (i) protect against the deleterious effects of noxious agents and ensure the conservation of resources that are needed to survive under adverse conditions or (ii) activate apoptosis. In this article, we have reviewed several lines of evidence which support the notion that regulation of translation initiation is an important component of the cellular stress response. While the stress-induced post-translational regulation of translation initiation factors (eIFs) has been well documented, stress-induced regulation of eIFs at the mRNA levels, as reviewed here, is only beginning to be elucidated. Thus, the stress-mediated regulation of eIFs occurs at multiple different levels involving, transcriptional, post-transcriptional and post-translational controls.