Psoriasin is an abundant low molecular weight protein in keratinocytes from psoriatic lesions. Because of similarities in gene structure and expression to other genes on human chromosomal band 1q21, we hypothesized that psoriasin might also map to this region. To test this hypothesis, we identified and used a genomic lambda clone (lambda 9.2) as a probe for fluorescent in situ hybridization. lambda 9.2 detected the 1q21 region in 81% of 52 chromosomes 1 examined, although it also hybridized to acrocentric chromosomes. lambda 9.2 DNA yielded polymerase chain reaction amplification of 121-bp sequence colinear with psoriasin cDNA, as did genomic DNA from hybrid cell lines containing all or part of chromosome 1. The psoriasin gene was present on a 380-kb yeast artificial chromosome clone that was previously mapped to 1q21 and shown to contain calcyclin; here it is also shown to contain MRP8 and CaN19. Psoriasin and several other tightly linked 1q21 genes were markedly overexpressed in psoriatic lesions, suggesting a role for these clustered genes in the regulation of epidermal proliferation.