The use of NSAIDs (nonselective inhibitors of cyclooxygenase (COX-1 and COX-2)) and coxibs (selective COX-2 inhibitors) is a mainstay of anti-inflammatory and analgesic therapy. Since these agents act at the level of PGH2 synthesis in the prostaglandin (PG) pathway, the question arises whether selective inhibition of downstream PG synthesizing enzymes like microsomal prostaglandin E2 synthase-1 (mPGES-1) could yield similar or greater efficacy. mPGES-1 is an inducible enzyme primarily coupled to COX-2, and studies of mPGES-1 null mice have defined its significant role in mediating pain, inflammation, fever, arthritis, atherosclerosis, stroke, and cancer. This review outlines the rationale for targeting mPGES-1 and summarizes the progress in developing selective mPGES-1 inhibitors (including fatty acid and PGH2 analogues, indole derivatives, phenanthrene imidazoles, and other classes) as well as their efficacy in preclinical models of inflammation and pain.