We discuss novel insight into the role and consequences of the phosphorylation of the translation initiation factor eIF2α in the context of stress responses and cell-cycle regulation. eIF2α is centrally located to regulate translation and its phosphorylation in response to different environmental challenges is one of the best characterized stress-response pathways. In addition to its role in stress management, eIF2α phosphorylation is also linked to cell-cycle progression and memory consolidation in the nervous system. The best known consequences of eIF2α phosphorylation are downregulation of global translation and stimulation of translation of some mRNAs. However, recent evidence shows that (i) eIF2α phosphorylation is not always required for the downregulation of global translation after exposure to stress and (ii) eIF2α phosphorylation does not necessarily lead to the downregulation of global translation. These results suggest that the textbook view of eIF2α phosphorylation needs to be revised and that there must be additional regulatory mechanisms at play.