Oxalate, a metabolic end product, is an important factor in the pathogenesis of renal stone disease. Oxalate exposure to renal epithelial cells results in re-initiation of the DNA synthesis, altered gene expression and apoptosis but the signaling pathways involved in these diverse effects have not been evaluated. The effects of oxalate on mitogen- and stress-activated protein kinase signaling pathways were studied in LLC-PK1 cells. Exposure to oxalate (1mM) rapidly stimulated robust phosphorylation and activation of p38 Mitogen-activated Protein Kinase (p38MAP kinase). Oxalate exposure also induced modest activation of c-Jun N-terminal Kinase (JNK), as monitored by phosphorylation of c-Jun. In contrast, oxalate exposure had no effect on phosphorylation and enzyme activity of p42/44 MAP kinase. We also show that specific inhibition of p38 MAP kinase by SB203580 (4(4-(fluorophenyl)-2-(4-methylsulfonyl-phenyl)-5-(4-pyridyl) imidazole) or by over-expression of a Kinase-dead dominant negative mutant of p38 MAP kinase, abolishes oxalate induced re-initiation of DNA synthesis in LLC-PK1 cells. The inhibition is dose dependent and correlates with in situ activity of native p38 MAP kinase, determined as Mitogen-activated Protein Kinase Activated Protein Kinase-2 (MAPKAP kinase-2) activity in cell extracts. Thus, this study not only provides the first demonstration of selective activation of p38 MAP kinase and JNK signaling pathways by oxalate but also suggests that p38 MAP kinase activity is essential for the effects of oxalate on re-initiation of DNA synthesis.