Cyclooxygenase-2 (COX-2) may modulate atherosclerotic plaque stability or instability according to the prostaglandin synthase coupled with it. Whereas upregulation of COX-2 and prostaglandin ( PG) E synthase is associated with plaque instability, overexpression of COX-2 and lipocalin-type PGD synthase leads to plaque stability. Thus, the role of COX-2 in atherothrombosis appears to be quite complex. In this article we summarize our recent papers investigating mechanisms regulating the expression and pharmacologic modulation of COX-2 in atherosclerotic plaques.