Siphonodictyal B1 is a sesquiterpene-hydroquinone isolated from the Caribbean coral reef bioeroding sponge Siphonodictyon coralliphagum. Siphonodictyal B1 increased intracellular calcium levels in neuroendocrine cells (PC12) in the presence and absence of extracellular calcium using Fura-2 as a calcium-sensitive dye. The calcium rise was comparable in amplitude and timing to the application of the sarco-endoplasmic reticulum calcium-ATPase (SERCA) inhibitor thapsigargin from the terrestrial plant Thapsia garganica. The effects of thapsigargin and siphonodictyal B1 on intracellular calcium levels were not distinguishable in pharmacological experiments conducted with caffeine, ryanodine, muscarine, and thapsigargin in calcium-free and calcium-containing buffer, although thapsigargin was effective at lower concentrations. Thapsigargin is a sesquiterpene-lactone and has no structural similarities to siphonodictyal B1. We conclude that thapsigargin and siphonodictyal B1 share SERCAs as cellular targets. Siphonodictyal B1 may be involved in the process of bioeroding the calcium carbonate endoskeleton of the scleractinian corals attacked by S. coralliphagum.