The complete protein precursor of human kidney renin has been determined from the sequence of cloned genomic DNA. The gene spans 12 kilobases of DNA and is interrupted by eight intervening sequences. The nine regions (exons) encoding the protein were mapped with a mouse renin cDNA probe, synthetic oligonucleotide probes, and by hybridization of genomic restriction fragments to a 1600-nucleotide human kidney mRNA. The predicted 403-amino acid preprorenin consists of mature renin and a 66-residue amino-terminal prepropeptide. The DNA sequence 5' to the first exon indicates the location of a transcriptional promoter (T-A-T-A-A-A) for a mRNA encoding preprorenin. An additional transcriptional promoter site is located within the first intron, which, if used, would express a shortened nonsecreted prorenin. The structure of the human renin gene is similar to that of human pepsinogen, a closely related aspartyl protease enzyme. This observation suggests that renin and pepsinogen have a common evolutionary origin.