Transcriptomic studies are useful for elucidating molecular mechanisms through which changes in nutrient availability produce pleiotropic effects on whole-body and tissue physiology. To further the knowledge of gene-regulatory effects of Zn on tissues important for adult and fetal Zn nutrition, we analysed the responses of human intestinal Caco-2 and placental JAR cells to changes in Zn supply. Analysis of oligonucleotide microarrays demonstrated that, despite the analogous roles of the two tissues in nutrient transfer, different genes respond to changes in Zn availability in intestinal cells compared with placental cells. A number of Fe- and Cu-related genes were identified as targets for regulation by Zn, revealing potential mechanisms underlying reported dietary interactions between Zn and other metals. We established that there are fundamental differences in Zn-regulated transcriptional control in Caco-2 compared with JAR cells. We demonstrated that Zn-induced transcriptional activation of the metallothionein 2A promoter occurs over different, and physiologically relevant, concentration ranges in Caco-2 and JAR cells, indicating that these cell lines sense changes in the extracellular Zn concentration over different ranges. Also, we established that mRNA levels of the Zn-responsive metal response element binding transcription factor (MTF)-1, and its homologue MTF-2, are regulated by Zn in Caco-2 but not JAR cells, which may in part underlie differential gene responses to Zn in intestinal and placental cells. The present study identified a number of novel molecular targets that may underlie symptoms associated with deficient or excessive Zn supply and highlighted the necessity of taking account of cell- and tissue-specific processes when investigating Zn-regulated gene expression in mammals.