Two new sesterterpene metabolites, 16-acetoxy-dihydrodeoxoscalarin (1) and astakolactin (2), were isolated from the sponge Cacospongia scalaris, collected from the gulf of Astakos, Greece, along with furoscalarol (3) and deoxoscalarin (4), which have not been reported from C. scalaris in the past. The unpalatability of the sponge to fish was traced by field feeding assays to the fractions containing dihydrofurospongin-2. The structures of the new metabolites were elucidated by interpretation of their NMR data and high-resolution mass spectral measurements.