Cancer cells have long been noted for alterations in centrosome structure, number, and function. Colorectal cancers are interesting in this regard since two frequently mutated genes, APC and CTNNB1 (β-catenin), encode proteins that directly interact with the centrosome and affect its ability to direct microtubule growth and establish cell polarity. Colorectal cancers also frequently display centrosome over-duplication and clustering. Efforts have been directed toward understanding how supernumerary centrosomes cluster and whether disrupting this clustering may be a way to induce aberrant/lethal mitoses of cancer cells. Given the important role of the centrosome in establishing spindle polarity and regulating some apoptotic signaling pathways, other approaches to centrosome targeting may be fruitful as well. Basic information on the nature and extent of centrosome defects in colorectal cancer, including why they over-duplicate and whether this over-duplication compensates for their functional defects, could provide a framework for the development of novel approaches for the therapeutic targeting of colorectal cancer.