The viequeamides, a family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya) containing cyclic depsipeptides, were isolated from a shallow subtidal collection of a ‘button’ cyanobacterium (Rivularia sp.) from near the island of Vieques, Puerto Rico. Planar structures of the two major compounds, viequeamide A (1) and viequeamide B (2), were elucidated by 2D-NMR spectroscopy and mass spectrometry, whereas absolute configurations were determined by traditional hydrolysis, derivative formation, and chromatography in comparison with standards. In addition, a series of related minor metabolites, viequeamide C–F (3–6), were characterized by high resolution mass spectroscopic (HRMS) fragmentation methods. Viequeamide A was found to be highly toxic to H460 human lung cancer cells (IC50 = 60 ± 10 nM), whereas the mixture of B–F was inactive. From a broader perspective, the viequeamides help to define a “superfamily” of related cyanobacterial natural products, the first of which to be discovered was ‘kulolide’. Within the kulolide superfamily, a wide variation in biological properties is observed, and the reported producing strains are also highly divergent, giving rise to several intriguing questions about structure-activity relationships and the evolutionary origins of this metabolite class.