Phosphorylation of eukaryotic initiation factor-2 (eIF-2) is an important mechanism regulating general translation initiation. Two mammalian eIF-2 kinases, the double-stranded-RNA-dependent kinase (PKR) and heme-regulated inhibitor kinase (HRI), have been characterized by sequencing, revealing shared sequence and structural features distinct from other eukaryotic protein kinases. Recent work in yeast has shown that a third related kinase, GCN2, also phosphorylates the regulated site in eIF-2. However, unlike the mammalian kinases, this kinase regulates gene-specific translation. Current models are presented for the regulation of each eIF-2 kinase, and the molecular basis for how this general form of regulation is adapted to control expression of a single species of messenger RNA is discussed.