Theopederins K (1) and L (2) have been isolated from the marine sponge Discodermia sp. collected from Honduras. 1 and 2 showed in vitro cytotoxicity against P-388 and A-549 cell lines. Marine sponges belonging to the genus Discodermia are a promising source of diverse chemical metabolites having a variety of bioactivities. In a continuing search for new cytotoxic agents from the genus Discodermia, we have isolated two new natural products that showed remarkable cytotoxicity against P-388 murine leukemia and A-549 human lung adenocarcinoma cell lines. These cytotoxic agents, trivially named theopederin K (1) and theopederin L (2), are 17-methoxy-6-hydroxy-18-en-theopederin G and 6-hydroxy-18-en-theopederin G, respectively, and have not been previously described in the literature. The structures were determined by a combination of NMR and mass spectral studies and by comparison with the NMR data of related compounds reported in the literature. Here, we report the isolation of theopederins K and L from the sponge genus Discodermia. It is remarkable to note that natural products incorporating the pederin skeleton with minor variations have now been isolated from five genera of the marine sponges, Mycale and Stylinos belonging to the order Poecilosclerida, Trachycladus belonging to the order Axinellida, Theonella and Discodermia belonging to the order Lithistida, as well as the blister beetle Paederus fuscipes. The presence of a rare class of alkaloids in such taxonomically distinct organisms may indicate a possible microbial biogenetic origin. The isolation, biological activities, and structure elucidation of theopederins K (1) and L (2) are described.