To sharpen the search for new lipoxygenase inhibitors, we designed a screen to probe for both potency and selectivity. The assay utilized 12-human (12-HLO), 15-human (15-HLO), and 15-soybean (15-SLO) lipoxygenases. The IC(50) value data obtained provided new insights about structure-activity relationships (SAR) for redox and nonredox inhibitors. All of the compounds tested were isolated from sponges and consisted of a novel terpenoid, hyrtenone A (1), and 12 known terpenoids. Potent compounds were defined as those having IC(50) values < 1 microM, and selectivity was assessed from the three possible IC(50) value ratios. One of the four terpenoid redox inhibitors studied, puupehenone (2), was equivalent to or better in potency than the well-known redox inhibitor nordihydroguarierate acid (NDGA, 14). However, none of the terpene redox inhibitors exhibited a selectivity ratio on a par with that of 14. Several potent nonredox inhibitors were identified, and one, dimethoxypuupehenol (5), exhibited notable selectivity. The structural elucidation of 1 and the SAR results for 13 natural products are reported. This study suggests that sponge-derived terpenes are a promising source for new lipoxygenase inhibitors.