Despite the marked differences in their physiological roles, the structures and catalytic functions of the prostaglandin H2 endoperoxide synthases-1 and -2 (PGHS-1 and -2) are almost completely identical. These integral membrane proteins catalyze the conversion of arachidonic acid to PGG2 and finally to PGH2. The crystal structures of PGHS-1 and -2 provide new insights into the catalytic mechanism for fatty acid oxygenation. Moreover, a clearer picture emerges to explain how a handful of amino acid substitutions can give rise to subtle differences in ligand binding between the two isoforms. These "small" alterations of isozyme structure are sufficient to allow the design of new, isoform-selective drugs.