Extracts of the South African nudibranch Chromodoris hamiltoni were found to contain four unusual chlorinated homo-diterpenes, hamiltonins A-D (3a-6), and a new sesterterpene hamiltonin E (7), in addition to the known toxins latrunculins A (1) and B (2). As part of an ongoing investigation of secondary metabolites of South African marine invertebrates, seven specimens of the brilliantly colored nudibranch C. hamiltoni were collected by hand using scuba (-30 m) from Aliwal Shoal, near Durban, South Africa. The specimens were stored in acetone for approximately one month, extracted repeatedly with acetone, and the extracts were pooled and chromatographed on silica gel with a solvent gradient from hexane through dichloromethane and ethyl acetate to methanol. More polar fractions were further purified by normal phase HPLC to isolate latrunculins A-B (identified via mass spectra and NMR comparison with literature) and the new compounds: chlorinated homo-diterpenes hamiltonin A (3a), hamiltonin B (4a), hamiltonin C (5), hamiltonin D (6), and sesterterpene hamiltonin E (7). Structural elucidation of the new compounds utilized spectroscopic methods (HRFAB-MS, IR, 1H/13C NMR, COSY, HMQC, HMBC) and chemical derivatization (acetylation). Relative stereochemistry was determined from coupling constants and NOE difference experiments, while the absolute stereochemistry of hamiltonin E was established by CD spectroscopy. Gut content analysis revealed spicules typical of sponges of the genus Latrunculia. Hamiltonins A and B showed no significant activity in antimicrobial and cytotoxicity (HCT-116) bioassays. The diaxial conformation of the 5α-chloro,6β-hydroxyl substituents in hamiltonins A-D suggests their biosynthesis may proceed via chloride attack on a 5β,6β-epoxide intermediate, differing from the usual halonium ion-initiated cyclization proposed for most chlorinated metabolites from sponges or nudibranchs.