Metabolism of arachidonic acid leads to several families of lipid mediators, including prostaglandins, thromboxane, leukotrienes, and lipoxins, along two major metabolic pathways, the cyclooxygenase (COX) and lipoxygenase (LO) pathways. These compounds, collectively known as eicosanoids, possess potent biological activities and are involved in maintenance of normal hemostasis, regulation of blood pressure, renal function, and reproduction as well as host defense. When formed in excess under pathological conditions, these molecules can elicit pain, fever, and inflammation and play roles in many acute and chronic endemic diseases. In this article we will focus on the lipoxygenases and the leukotrienes (Figure 1). Although there are only two cyclooxygenases (COX-1 and COX-2) in man, there are no fewer than 6 lipoxygenases, one of which has been unequivocally linked to human disease, viz., 5-lipoxygenase (5-LO). Since the key discoveries in the mid 1970s, many comprehensive and highly cited review articles have appeared on the biochemistry and pathophysiological implications of lipoxygenases and leukotrienes. 1À4 It is now almost a decade since this topic was covered, and we believe that time is ripe to summarize and make an update of the most important knowledge that has evolved from the research field. We will walk the reader through basic lipoxygenase chemistry, describe 5-LO and leukotriene (LT) synthesis, including all key enzymes and the receptors that transduce leukotriene signaling, continue with the cellular and in vivo biology of lipoxygenases and leukotrienes, and finish with discussions of their roles in disease and possibilities for pharmacological interventions. In particular, we will integrate a basic biochemical understanding with recent developments in the field of structural biology and describe the most salient conclusions that can be drawn from work on transgenic mice, a powerful tool to define the in vivo biological and pathogenic roles of these enzymes. Extraction of results from more than three decades of research means that we cannot be complete, and we would therefore like to apologize to those distinguished colleagues whose work we have not found space to describe and cite.