Despite decades of research, corticosteroids and NSAIDs remain the main pharmacological weapons to control inflammation in the clinic. Unfortunately, these drugs have significant side effects, especially when used chronically. Consequently, there is tremendous interest in the development of novel, safer, and more effective anti-inflammatory drugs. Most antiinflammatory agents directly or indirectly inhibit the formation or the effects of arachidonic acid metabolites collectively known as eicosanoids (prostaglandins, leukotrienes, thromboxanes, endoperoxides, and other mediators)(Table 1). It has long been recognized that inhibition of phospholipase A2–catalyzed (PLA2-catalyzed) arachidonic acid release from cell-membrane glycerophospholipids could potentially block the synthesis of all eicosanoids. The vast PLA2 enzyme family includes cellular isoforms involved in signal transduction, such as three cellular isoforms of PLA2 (cPLA2s), and ten secretory isoforms of PLA2 (sPLA2s)(1). Various sPLA2 isoforms participate in digestive physiology, antimicrobial defense, and inflammation. The cPLA2s, and sPLA2s IIA and V, play key roles in arachidonic-acid release during acute inflammation (1). Two families of endogenous proteins include members whose synthesis and/or secretion are induced by glucocorticoids in the lung that exhibit anti-inflammatory activity in experimental models. These are the lipocortins, or annexins (2), and the secretoglobins, whose prototype is uteroglobin (3). These families include proteins with distinct and pleiotropic biological properties. Lipocortins I and V, as well as rabbit and human uteroglobin, have anti-inflammatory properties that can be explained, at least in part, by their ability to inhibit sPLA2. Human uteroglobin or “Clara Cell 10 kDa protein” is currently in clinical development for the prevention of airway inflammation in neonatal lung disease. The mechanism of sPLA2 inhibition by lipocortins and uteroglobin remains controversial and may depend on the assay system. However, a 9–amino acid sequence that is highly conserved in uteroglobin and the anti-inflammatory lipocortins I and V was identified as early as 1988 (4). Synthetic peptides corresponding to this shared sequence exhibit striking anti-inflammatory activity in vivo and inhibit sPLA2 in vitro. Mutagenesis data show that this sequence is necessary for sPLA2 inhibition by uteroglobin (5). Peptides derived from