Actin and tubulin are the two major proteins of the cytoskeleton in eukaryotic cells and both display a common property to reversibly assemble into long and flexible polymers, actin filaments and microtubules, respectively. These proteins play important roles in a variety of cellular functions and are also involved in numbers of diseases. An emerging number of marine-derived cytotoxins have been found to bind either actin or tublin, resulting in either inhibition or enhancement of polymerization. Thus, these toxins are valuable molecular probes for solving complex mechanisms of biological processes. This chapter describes actin- and tubulin-targeting marine natural products and their modes of action, with reference to their use as research tools and their clinical applications.