A human 15-lipoxygenase (15-HLO) assay has been employed to discover new marine-sponge-derived bioactive compounds. Extracts from two different sponges, Jaspis splendens (order Choristida, family Jaspidae) and Suberea sp. (order Verongida, family Aplysinellidae), exhibited potent IC(50) values of 0.4 and 0.1 microg/mL, respectively. Both are sources of terpenoids, and the former is a known source of (+)-jasplakinolide (7), which is inactive as a 15-HLO inhibitor. The terpenoids included (+)-(5S,6S)-subersin (1, IC(50) > 100 microM), (-)-(5R,10R)-subersic acid (2, IC(50) = 15 microM), jaspaquinol (3, IC(50) = 0.3 microM), and (-)-jaspic acid (4, IC(50) = 1.4 microM). Structure elucidations and lipoxygenase activity studies of these compounds are reported.