The guineamides (1-6) are novel cyclic depsipeptides isolated and characterized from a Papua New Guinea collection of the marine cyanobacterium Lyngbya majuscula. The planar structures of these new natural products were established using an extensive array of 1D and 2D NMR experiments, including HSQC, TOCSY, and HMBC. Absolute stereochemistry was determined using a combination of chemical manipulations as well as Marfey's method. These metabolites all contain beta-amino or beta-hydroxy carboxylic acid residues, an increasingly common feature in marine cyanobacterial metabolites. The identification of 2,2-dimethyl-3-hydroxyhexanoic acid (Dmhha) in guineamides E (5) and F (6) represents the first report of such a residue in a natural product. In addition, characterization of the unique beta-amino acid 2-methyl-3-aminopentanoic acid (Mapa) in guineamide A (1), which has also been reported as a component of several marine molluscan metabolites, especially from those of Dolabella auricularia, further supports the diet-derived nature of such compounds as isolated from marine invertebrates. Guineamides B (2) and C (3) possess moderate cytotoxicity to a mouse neuroblastoma cell line with IC(50) values of 15 and 16 microM, respectively.