AbstractThe classical role of the conserved Gcn2 kinase of yeast and mammals is to activate the translation of the transcription factors Gcn4 in yeast and activating transcription factor 4 in mammals by phosphorylating the eukaryotic translation initiation factor 2α. Gcn2 is activated by uncharged tRNAs in response to amino acid starvation and this regulatory system is important for tolerance to nutrient deprivation and other stresses and for development, differentiation, and normal function of mammalian organs. In the past few years, the classical Gcn2 pathway has been shown to modulate life span, tumor cell survival, and immune responses. In addition, Gcn2 modulates translation of novel mRNAs such as those of an unknown regulator of leucine transport and of sulfiredoxin SRX1 in yeast (activation of translation) and of inducible nitric oxide synthase, ErBb2, HIF1a, and 5′‐terminal oligopyrimidine tract mRNAs in mammals (inhibition of translation). Finally, Gcn2 directly phosphorylates novel proteins such as methionyl‐tRNA synthetase in mammals, and this triggers a pathway for DNA repair. These findings anticipate many expanding roles of Gcn2 in the future, with relevance for stress responses and human disease. © 2012 IUBMB IUBMB Life, 64(12): 971–974, 2012