Background: Deposition of crystals within tubular lumens is a feature of many kidney stone diseases, including crystals of calcium oxalate monohydrate (COM) in primary hyperoxaluria and of 2,8-dihydroxyadenine (DHA) in adenine phosphoribosyltransferase deficiency. Crystals are injurious to renal epithelial cells, but the molecular bases of cell injury have not been well characterized. Methods: We used a cDNA microarray to identify the time-dependent changes in gene expression associated with the interaction of COM or DHA crystals with primary cultures of normal human kidney cortical epithelial cells. Results: We observed gene expression changes that were common to both crystal types, as well as a number of crystal-specific responses. A subset of genes known to be aberrantly expressed in kidney tissue from stone formers also showed an altered expression in COM- or DHA-treated normal human kidney cortical epithelial cells. Conclusions: Our results show that cultured epithelial cells exposed to COM or DHA crystals demonstrate cellular responses that may be physiologically relevant, thus suggesting that this experimental system may be useful for elucidating the mechanisms of crystal-induced renal cell injury.