Terrestrial actinomycetes or filamentous bacteria produce a large number of antibiotic and associated compounds. For the past years, we have explored the biosynthetic potential of diverse classes of marine bacteria to determine whether they produce secondary metabolites that extend the molecular diversity of their terrestrial counterparts. Uniquely adapted actinomycetes exist in marine habitats, and these habitats include the surfaces of animals and plants as well as shallow water sediments. Previous reports have documented the production of new antibiotics and antitumor agents from this source. In this Communication, we augment these earlier observations by reporting the structures of the salinamides A and B, anti-inflammatory cyclic depsipeptides with unusual structures. The salinamide-producing actinomycete was isolated from the surface of the jellyfish Cassiopeia xamachana collected in the Florida Keys. Salinamides A and B are related as epoxide and chlorohydrin. The structure of salinamide B was established by single crystal X-ray diffraction analysis, and absolute stereochemistry was set by chiral GC analysis of hydrolytic fragments. The core of salinamide B is a bicyclic hexadepsipeptide with two ester links involving serine and an aromatic ether link. Salinamides A and B exhibit moderate antibiotic activity against Gram-positive bacteria, with the most potent in vitro activity against Streptococcus pneumoniae and Staphylococcus pyogenes (MIC values of 4 μg/mL for salinamide A and 4 and 2 μg/mL for salinamide B). More importantly, they show potent topical anti-inflammatory activity using the phorbol ester-induced mouse ear edema assay, with salinamide A inhibiting edema by 84% and salinamide B by 83% at the standard testing dose of 50 μg/ear.