While isolation of alkaloids from marine Porifera has been accelerating, only a small number of antineoplastic or peptide constituents have been recovered from these invertebrates. Our isolation and structural determination of the P388 lymphocytic leukemia cell growth inhibitory cyclooctapeptide hymenistatin 1 from a Palau sponge in the genus Hymeniacidon represented the first such combination of source, structural type, and biological activity. We found an Axinella sp. (Demospongiae class) collected in Palau (1979, ~40 m) to yield a methylene chloride-2-propanol extract that provided a 101% increase in life span (at 100 mg/kg) against P38 leukemia with ED50 2.5 μg/mL. In 1985, the sponge was recollected and preserved in 2-propanol. A 220-kg (wet weight) portion was extracted with methylene chloride-methanol. By P38 guided bioassay and a series of chromatographic techniques, a series of structurally diverse antineoplastic constituents were detected, including the most potent in vivo components homohalichondrin B (1, 4.1 × 10⁻⁶% yield, P38 T/C 285 at 150 μg/kg) and halichondrin B (2, 1.8 × 10⁻⁶% yield, T/C 238 at 25 μg/kg), a new P38 inhibitory peptide axinastatin 1 (3, 4.54 × 10⁻⁴% yield, ED50 0.21 μg/mL), along with axinhydantoin (30 mg) and hymenialdisine (0.53 mg). Axinastatin 1 (3) is a cycloheptapeptide with all L-configured amino acids, characterized by crystallization, optical rotation, TLC, UV, IR, high-resolution FAB MS, 2D NMR, and chiral GC analysis. The halichondrins proved remarkably potent against all 60 cell lines in the U.S. NCI's human tumor cell line in vitro screen, with a distinctive mean graph profile highly correlated to tubulin-binding agents like vincristine and taxol. Discovery of the halichondrins in Axinella sp., unrelated to their original source, suggests these constituents may have a microorganism origin. Marine Porifera continue to be a fruitful source of potentially useful antineoplastic substances of novel structure.