Chromosome instability, which is equated to mitotic defects and consequential chromosome segregation errors, provides a formidable basis for the acquisition of further malignant phenotypes during tumour progression. Centrosomes have a crucial role in the formation of bipolar mitotic spindles, which are essential for accurate chromosome segregation. Mutations of certain oncogenic and tumour-suppressor proteins directly induce chromosome instability by disrupting the normal function and numeral integrity of centrosomes. How these proteins control centrosome duplication and function, and how their mutational activation and/or inactivation results in numeral and functional centrosome abnormalities, is discussed in this Review.