Microsomal prostaglandin E synthase 1 (mPGES-1) is an ?-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E<
sub>
2<
/sub>
(PGE<
sub>
2<
/sub>
) from prostaglandin H<
sub>
2<
/sub>
(PGH<
sub>
2<
/sub>
). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH<
sub>
2<
/sub>
synthesis and avoiding suppression of antithrombotic prostacyclin production. In this work, we determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure?activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.