The biosynthesis of histidine in Escherichia coli and Salmonella typhimurium has been an important model system for the study of relationships between the flow of intermediates through a biosynthetic pathway and the control of the genes encoding the enzymes that catalyze the steps in a pathway. This article provides a comprehensive review of the histidine biosynthetic pathway and enzymes, including regulation of the flow of intermediates through the pathway and mechanisms that regulate the amounts of the histidine biosynthetic enzymes. In addition, this article reviews the structure and regulation of the histidine ( his ) biosynthetic operon, including transcript processing, Rho-factor-dependent “classical” polarity, and the current model of his operon attenuation control. Emphasis is placed on areas of recent progress. Notably, most of the enzymes that catalyze histidine biosynthesis have recently been crystallized, and their structures have been determined. Many of the histidine biosynthetic intermediates are unstable, and the histidine biosynthetic enzymes catalyze some chemically unusual reactions. Therefore, these studies have led to considerable mechanistic insight into the pathway itself and have provided deep biochemical understanding of several fundamental processes, such as feedback control, allosteric interactions, and metabolite channeling. Considerable recent progress has also been made on aspects of his operon regulation, including the mechanism of pp(p)Gpp stimulation of his operon transcription, the molecular basis for transcriptional pausing by RNA polymerase, and pathway evolution. The progress in these areas will continue as sophisticated new genomic, metabolomic, proteomic, and structural approaches converge in studies of the histidine biosynthetic pathway and mechanisms of control of his biosynthetic genes in other bacterial species.