The serpins are a superfamily of gene sequences that have been conserved through evolution. These genes encode protein products that perform a variety of functions in vivo, and their regulation differs among different cell types. About one-third of the serpin genes in the human genome are located at 14q32.1, and the serpin genes in this ~370 kb region are organized into discrete proximal, central, and distal subclusters of four, three, and four genes each. In this report we discuss the genomic organization of the 14q32.1 serpin gene cluster, and we summarize what is known about the regulation of each serpin gene in this region. An approach for studying locus-wide regulation of chromosomal serpin genes in situ is also described. Using this approach, specific mutations in the proximal serpin subcluster were prepared by homologous recombination. These mutant alleles define a serpin locus control region that regulates gene activity and chromatin structure of the entire proximal subcluster. Prospects for further analyses of this complex genomic domain are discussed.