Pitipeptolide A is the major secondary metabolite in a persistent population of the cyanobacterium Lyngbya majuscula from Guam. Because this cyanobacterium is of low preference to many sympatric consumers, we tested the hypothesis that this compound acted as a chemical defense. Pitipeptolide A was deterrent to urchins, two species of amphipods, and small herbivorous crabs, whereas it did not deter feeding by the sea hare Stylocheilus striatus, which readily consumes cyanobacteria. Although our comparison included various small invertebrates, which are often tolerant to algal chemical defenses, this cyanobacterial compound proved deterrent at natural concentrations to all but one of the consumer species tested. Thus, the production of defensive secondary metabolites is likely related to the common occurrence of L. majuscula on this coral reef despite the abundance of diverse grazers.