Enzymes, such as protein kinase C (PKC), are ubiquitously expressed by eukaryotes and are an attractive target to guide discovery of new bioactive substances. The PKC signaling path constitutes a pivotal mechanism in the regulation of fundamental processes such as protein synthesis, gene expression, and cell proliferation. Consequently, the development of selective, nontoxic PKC inhibitors may provide treatments for cancer or viruses. Only a few natural product PKC inhibitors have been discovered, and some of the most important are alkaloids such as the staurosporines, chelerythrine, and balanol. We report below xestocyclamine A (1) as a new type of polycyclic alkaloid PKC inhibitor. The work leading to the discovery of xestocyclamine A (1) began when the semipure extracts of Xestospongia sp., a soft, brown, massive sponge collected from the Milne Bay province of Papua, New Guinea, exhibited 100% inhibition at 5 mu g/mL against PKC beta .