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A polyoxygenated and halogenated labdane, spongianol (<b>1</b>); a polyoxygenated steroid, 3β,5α,9α-trihydroxy-24<i>S</i>-ethylcholest-7-en-6-one (<b>2</b>); a rare seven-membered lactone B ring, (22<i>E</i>,24<i>S</i>)-ergosta-7,22-dien-3β,5α-diol-6,5-olide (<b>3</b>); and an α,β-unsaturated fatty acid, (<i>Z</i>)-3-methyl-9-oxodec-2-enoic acid (<b>4</b>) as well as five known compounds, 10-hydroxykahukuene B (<b>5</b>), pacifenol (<b>6</b>), dysidamide (<b>7</b>), 7,7,7-trichloro-3-hydroxy-2,2,6-trimethyl-4-(4,4,4-trichloro-3-methyl-1-oxobu-tylamino)-heptanoic acid methyl ester (<b>8</b>), and the primary metabolite 2’-deoxynucleoside thymidine (<b>9</b>), have been isolated from the Red Sea sponge <i>Spongia</i> sp. The stereoisomer of <b>3</b> was discovered in <i>Ganoderma resinaceum</i>, and metabolites <b>5</b> and <b>6</b>, isolated previously from red algae, were characterized unprecedentedly in the sponge. Compounds <b>7</b> and <b>8</b> have not been found before in the genus <i>Spongia</i>. Compounds <b>1</b>–<b>9</b> were also assayed for cytotoxicity as well as antibacterial and anti-inflammatory activities.