The mechanism by which chemical inducers of the stress response inhibit protein synthesis was examined. All the chemicals tested principally inhibit the initiation phase of translation. Covalent modification of the initiation factor proteins does not constitute a common mechanism. Eukaryotic initiation factor (eIF)-2 alpha phosphorylation is moderately to strongly induced by Na arsenite and diamide, but only slightly to imperceptibly affected by iodoacetamide, azetidine carboxylic acid, and canavanine. eIF-4B dephosphorylation does not occur in any case. The only consistent change detected is the hyperphosphorylation of the 28,000 Da heat stress protein. These results indicate that these diverse chemicals, all of which enhance the transcription of the stress mRNAs, do not inhibit translation by a common, recognized mechanism; it is likely that several distinct pathways leading to inhibition exist.