Marine sponges continue to be a rich source of structurally novel cytotoxic secondary metabolites that are of interest as potential lead compounds for the development of new anticancer drugs. As part of an ongoing search for new cytotoxins from tropical sponges, it was found that extracts of Xestospongia exigua (Kirkpatrick) collected in Papua New Guinea exhibited a unique profile of selective in vitro cytotoxicities against a panel of human cancer cell lines. Bioassay-guided fractionation of the X. exigua extracts led to the isolation of a mixture of motuporamines A (1), B (2), and C (3) along with known members of the petrosin and xestospongin/araguspongine class of 3-alkylpiperidine alkaloids. The motuporamines, which contain a spermidine-like substructure, represent a new family of cytotoxic sponge alkaloids that appear to be biogenetically derived from the same basic building blocks, ammonia, acrolein, and a long-chain dialdehyde, involved in the Baldwin/Whitehead pathway to the 3-alkylpiperidine alkaloids isolated from marine sponges in the order Haplosclerida.