A collection of an undescribed marine sponge of the genus Plakortis yielded four new "polyketide-derived" metabolites, lehualides A-D (1-4). The structures of compounds 1-4 were elucidated by interpretation of spectral data. Compound 2 demonstrated cytotoxicity against an ovarian cancer cell line, while compound 4 was active against both ovarian cancer and leukemia cell lines.