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Kinetic studies on the derepression of 5 of the 10 enzymes for histidine biosynthesis in Salmonnella typhimurium reveal that derepression may proceed by two different modes, depending upon the site of mutation in the various histidine auxotrophs examined. Simultaneous derepression of the enzymes is observed in those mutants incapable of producing the intermediate, 4-amino-5-imidazolecarboxamide ribonucleotide, through the histidine pathway. Derepression of the enzymes in a temporal sequence corresponding to the positional sequence of the genes in the histidine operon is observed in those mutants which do produce this intermediate. The addition of 4-amino-5-imidazolecarboxamide ribonucleoside to cultures of mutants ordinarily characterized by the simultaneous mode of derepression served to shift the mode from simultaneous to sequential, but did not influence the derepressed rate of enzyme synthesis. In organisms in which the sequential mode is ordinarily observed, adenine effected a shift to the simultaneous mode, causing all the enzymes to derepress at the same time, but did not influence the derepressed rate of enzyme synthesis. Chloramphenicol, at low concentrations, reduced the growth rate of derepressed cells by a factor of 2 to 3 and decreased the rate of derepression of the histidine enzymes in all organisms tested. In the histidine auxotroph, hisE11, and in the wild type, LT-2 (derepressed by the addition of thiazole alanine), chloramphenicol prolonged the intervals between the times of derepression of the histidine enzymes. On the other hand, in hisG52, in which the enzymes for histidine biosynthesis derepress simultaneously and not sequentially, chloramphenicol did not alter the time of derepression of the enzymes. In the presence of chloramphenicol, adenine shifted the mode of derepression of hisE11 and LT-2 from sequential to simultaneous, just as it did in the absence of chloramphenicol. However, adenine did not eliminate the effect of chloramphenicol on the rate of depression. The data presented here suggest that the histidine operon is transcribed into a polycistronic message which, under conditions in which sequential derepression is observed, is translated from one end only. Under conditions in which simultaneous derepression is observed, the translation of this message is initiated at multiple sites.