A novel antifungal cyclic depsipeptide, cyclolithistide A (1), was isolated from a marine sponge, Theonella swinhoei. The structure of cyclolithistide A, which contains the unique amino acids 4-amino-3, 5-dihydroxyhexanoic acid, formyl-leucine, and chloroisoleucine, was elucidated through a combination of spectroscopic techniques. Thirteen additional specimens of T. swinhoei and three of Theonella conica were examined in this study. Many contained the two cyclic peptides, motuporin (2) and theonellapeptolide 1d (3), as major components, but none of these were a source of 1. The rationale behind this study and some additional aspects of these unusual results are presented.