Terrestrial actinomycetes 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 including the surfaces of animals and plants as well as shallow water sediments, with previous reports documenting the production of new antibiotics and antitumor agents from this source. Here, we report the structures of 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. Fermentation in seawater-based media, followed by double EtOAc extraction of the whole-broth suspension, vacuum-flash chromatography, and reversed-phase HPLC, yielded salinamide A (approximately 9% of the dry extract). A subsequent fermentation yielded salinamide B, whose structure was established by single crystal X-ray diffraction analysis, with absolute stereochemistry set by chiral GC analysis of hydrolytic fragments. Salinamides A and B are related as epoxide and chlorohydrin, representing a new class of bicyclic hexadepsipeptides with structural components (α-(hydroxyphenyl)glycine residue and non-peptide portions) either unknown or of limited distribution in other naturally occurring compounds. They exhibit moderate antibiotic activity against Gram-positive bacteria (e.g., MIC values of 4 μg/mL for salinamide A and 4/2 μg/mL for B against Streptococcus pneumoniae and Staphylococcus pyrogenes) and, more importantly, potent topical anti-inflammatory activity in the phorbol ester-induced mouse ear edema assay: 84% inhibition by A and 83% by B at the standard dose of 50 μg/ear.