Oxicams are a class of non-steroidal anti-inflammatory drugs (NSAIDs) structurally related to the enolic acid class of 4-hydroxy-1,2-benzothiazine carboxamides. They are used clinically to treat both acute and chronic inflammation by inhibiting the activity of the two cyclooxygenase (COX) isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Oxicams are structurally distinct from all other NSAIDs, exhibiting a novel binding pose in the COX channel. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding while two coordinated water molecules mediate a polar interaction between the oxicam and COX. The rotation of Leu-531 in the complex opens a new pocket, which is not utilized for binding other NSAIDs to the enzyme. This structure provides the basis for understanding documented structure-activity relationships (SAR) within the oxicam class. In addition, from the oxicam template, a series of potent microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors represents a new direction for drug development. Here, we review the major route of oxicam synthesis and SAR for COX inhibition, as well as recent advances in oxicam-mediated mPGES-1 inhibition.