<p>The cytoskeleton is a dynamic intracellular protein network composed of actin filaments, microtubules and intermediate filaments that provides structural support in cells and plays a crucial role in tumor metastasis. Tumor cells encounter various dynamic mechanical environments during metastasis, and they adapt to these environments through cytoskeletal reorganization, which enables them to regulate cell morphology, generate intracellular forces and induce intracellular signaling. Actin filaments contribute to migration and extracellular matrix degradation by forming protrusive structures, such as lamellipodia, filopodia and invadopodia. Microtubules support migration, stabilize cell polarity and enhance survival under shear stress. Intermediate filaments maintain structural integrity and mechanical flexibility, allowing cancer cells to pass through narrow spaces. The cytoskeleton’s pivotal role in regulating metastasis makes it a promising drug target. However, cytoskeleton-targeting drugs often face the challenges of nonspecificity and drug resistance. Recent advancements in the field have tried to overcome these limitations through selective targeting, drug delivery systems, antibody–drug conjugates and combination therapies. Here we summarize the roles and regulatory mechanisms of the cytoskeleton in metastasis and discusse the current cytoskeleton-targeting therapies, including their mechanisms, clinical applications and limitations. Furthermore, this review suggests future directions for developing effective and safe cytoskeleton-based interventions against metastasis.</p>