Exposure to the natural mineral fiber asbestos causes severe lung-damaging fibrosis and cancer, yet it continues to be used as an industrial insulating material throughout the world. When cultured human lung cells are exposed to asbestos, individual fibers are engulfed into the cytoplasm where they induce significant mitotic aberrations leading to chromosomal instability and aneuploidy. The mechanisms of how asbestosis ultimately leads to lung cancer remain unclear. However, our experiments indicate that intracellular asbestos fibers induce aneuploidy and chromosome instability by binding to a subset of proteins that include regulators of the cell cycle, cytoskeleton, and mitotic process. Moreover, precoating of fibers with protein complexes efficiently blocked asbestos-induced aneuploidy in human lung cells without affecting their uptake by cells. These results provide new evidence that asbestos fibers can contribute to significant spindle damage and chromosomal instability by binding to proteins needed for the assembly and regulation of the cytoskeleton or the cell cycle. Cell Motil. Cytoskeleton, 2006. © 2006 Wiley-Liss, Inc.