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Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium . Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. Access to enough material is needed for these studies, but samples of these compounds are limited due to the minute amounts that can only be obtained by either large-scale cultivation of the organism that produces them or by total synthesis. Of all the amphidinolides known to date, only the targets of five of them (B1, H1, J, K, and X) have been examined and all have been found to interact with actin, a crucial cytoskeletal protein. This paper reviews what is currently known about actin-interacting amphidinolides, with a focus on the research of our group. Amphidinolides J and X are F-actin destabilizers, whereas Amphidinolides H1 and K stabilize actin filaments, likely via different mechanisms. More precise details of the interaction between amphidinolides and actin are missing.