Investigation of the cytotoxic constituents of a two-sponge association (Poecillastra sp. and Jaspis sp.) led to the isolation of pectenotoxin II [1] and psammaplin A as the active compounds. In an in vitro cell culture assay, 1 displayed very potent cytotoxic activities against human lung (A-549), colon (HT-29), and breast (MCF-7) cancer cell lines. Pectenotoxin II also exhibited selective cytotoxicity against several cell lines representing ovarian, renal, lung, colon, CNS, melanoma, and breast cancer, with differences in LC50 values between sensitive and resistant cell lines of 100-fold or more.