The placental 11-hydroxysteroid dehydrogenase type 2 (11-HSD2; encoded by the HSD11B2 gene) has emerged as a key player in controlling fetal development, but its regulation is incompletely understood. Here we identified p38 MAPK as an important regulator of placental 11-HSD2. We showed that inhibition of p38 MAPK with the pharmacological inhibitor SB202190 led to a 50% reduction in 11-HSD2 activity, protein and mRNA in primary human placental trophoblast cells. Furthermore, the effect of SB202190 was confirmed by the use of two additional p38 inhibitors, SB203580 and SB220025. In addition, SB202190 decreased the half-life of 11-HSD2 mRNA without altering the HSD11B2 promoter activity, indicating that p38 MAPK regulates placental 11-HSD2 expression through modulation of 11-HSD2 mRNA stability. Importantly, siRNA-mediated knockdown of p38 caused a 50% reduction in 11-HSD2 activity, suggesting that p38 is the primary p38 isoform involved. Taken together, these findings suggest a novel pathway controlling placental 11-HSD2 expression resulting from the activation of p38 MAPK. Given that p38 is abundantly expressed in the human placenta where its function is largely unknown, our present study also reveals 11-HSD2 as an important target through which p38 may regulate human placental function, and consequently fetal growth and development.