Stylized cell depicting the mechanism of action of ibuprofen (IBU). Arachidonic acid is released from the cell membrane phospholipids by phospholipase A2 (PLA2), encoded by PLA2G4A (cytosolic, calcium-dependent) and PLA2G2A (in platelets and synovial fluid). Arachidonic acid is converted to the unstable intermediate prostaglandin (PG) H2 by cytosolic prostaglandin G/H synthases, termed cyclooxygenases (COX), that exist in two forms, COX-1 and COX-2, and are encoded by PTGS1 and PTGS2, respectively. PGH2 is converted by tissue-specific synthases to various prostanoids – that is, PGE2, PGD2, PGF2α, PGI2, and TxA2. These bioactive lipids act through their corresponding receptors to trigger a series of biological effects. Ibuprofen exerts its anti-inflammatory and analgesic effects through inhibition of both COX isoforms. In addition, ibuprofen scavenges HO•, •NO, and ONOO− radicals and can potentiate or inhibit nitric oxide formation through its effects on nitric oxide synthase (NOS) isoforms. Ibuprofen may activate the antinociceptive axis through binding to the cannabinoid receptors and through inhibition of fatty acid amide hydrolase (FAAH), which metabolizes the endocannabinoid anandamide. CNR1 and CNR2, cannabinoid receptors 1 and 2; H2O2, hydrogen peroxide; FAAH, fatty acid amide hydrolase; •NO, nitric oxide; NOS, nitric oxide synthase; ONOO−, peroxynitrite anion; O2•−, superoxide anion; PGD2, prostaglandin D2; PGDS, prostaglandin D synthase; PGE2, prostaglandin E2; PGF2α, prostaglandin F2α; PGFS, prostaglandin F synthase; PGH2, prostaglandin H2; PGI2, prostacyclin; PTGDR, prostaglandin D receptors; PTGER, prostaglandin E receptors; PTGES, prostaglandin E synthase; PTGFR, prostaglandin F receptors; PTGIR, prostacyclin receptor; PTGIS, prostacyclin synthase; TBXA2R, TxA2 receptor; TBXAS1, thromboxane A synthase 1; TxA2, thromboxane A2. A fully interactive version is available online at http://www.pharmgkb.org/pathway/PA166121942.