<jats:p> The blue marine sponge cribrostatins 1 (1, 8.8 × 10<jats:sup>−6</jats:sup>% yield) and 2 (2, 3.1 × 10<jats:sup>−6</jats:sup>% yield) active against the P388 lymphocytic leukemia cell line (ED<jats:sub>50</jats:sub> 1.58 and 2.73 μg/mL respectively) have been isolated. The previously known isoquinolinequinones mimosamycin (3), renierone (4), and O-demethylrenierone (5) were also isolated and shown to display activity against the P388 cell line (ED<jats:sub>50</jats:sub> 0.73, 2.75, and 8.36 μg/mL, respectively). Importantly, both cribrostatin 1 and mimosamycin showed selective activity against all of the nine human melanoma cell lines employed by the U.S. National Cancer Institute. Structural determinations were accomplished utilizing high field nuclear magnetic resonance (400 MHz) and mass spectral studies. Confirmation of the cribrostatin 1 structure was achieved by X-ray crystallographic techniques.