Mechanisms regulating pregnancy-induced changes in renal function are incompletely understood. Few candidate genes have been identified and data suggest that alternate mechanisms remain to be elucidated. Our objective was to screen thousands of genes expressed in kidneys from mice throughout gestation to identify possible key regulators of renal function during pregnancy. Mouse complementary DNA microarrays were used to screen for differences in expression during pregnancy in C57BL/6 mice. Interesting candidate genes whose expression varied with pregnancy were further analyzed by reverse transcription-PCR and Northern blot. Expression was localized by in situ hybridization and immunohistochemistry. Follow-up immunohistochemical analyses in archival human kidney sections from the fetus, non-pregnant, and pregnant women were also performed. Histidine decarboxylase (HDC), the enzyme that synthesizes histamine, was markedly upregulated in the mouse kidney during pregnancy. HDC expression localized to proximal tubule cells of fetal and adult mice. Females showed strong expression in the juxtamedullary zone before pregnancy and upregulation in the superficial cortical zone (SCZ) by mid-gestation. Histamine colocalized with HDC. Male mice showed only low HDC expression. Similar expression patterns were observed in human kidneys. Our results show that HDC expression and histamine production are increased in the SCZ during pregnancy. If histamine acts as a vasodilator, we speculate that increasing production in the SCZ may increase renal blood flow to this zone and recruit superficial cortical nephrons during pregnancy.