The popular view that all nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the production of prostaglandins has been challenged by the discovery that they also affect a wide variety of cellular processes that are important for their therapeutic actions and side effects. Although recognition of the differential activities of new and established NSAIDs on the activities of the cyclooxygenases (COXs) affecting production of inflammatory prostaglandins (from COX-2) and those that are physiologically important (from COX-1) may have significance for the prostaglandin components of the underlying inflammatory and physiologic processes, there are important features of their chemical structures that determine the various cellular and biochemical actions of these agents. Several established NSAIDs have low propensity to cause gastrointestinal (GI) ulceration and bleeding that may relate to these drugs having unique pharmacokinetic characteristics (pro-drugs, protein binding, etc). They also have weak effects on the production of GI mucosal prostaglandins and have specific physicochemical characteristics such that they cause minimal damage to mucosal membranes or effects on nonprostaglandin-related cellular mechanisms important in mucosal defenses. Some of the new COX-2-selective drugs with methyl or amino-sulfonyl moieties have relatively high pKa values and other properties that are similar to established NSAIDs with low GI ulcerogenicity. These physicochemical properties may contribute to the low irritancy of the new COX-2-selective drugs quite apart from their sparing of COX-1 in the GI mucosa. With concerns that some established NSAIDs may accelerate cartilage destruction in osteoarthritis (OA), interest is now focusing on whether the COX-2-selective drugs may have a lower potential for this adverse effect by avoiding the inhibitory effects on cartilage proteoglycan metabolism seen with such drugs as indomethacin and the salicylates. Meloxicam appears to be without inhibitory effects on proteoglycan metabolism, but it remains to be seen if this translates into any beneficial actions on the progression of joint changes in OA observed radiologically or from magnetic resonance imaging.