The molecular mechanisms ensuring accurate chromosome segregation during meiosis and mitosis are critical to the conservation of euploidy (normal chromosome number) in eukaryotic cells. A dysfunctional kinetochore represents one possible source for chromosome instability (CIN) and the generation of aneuploidy. The kinetochore is a large complex of proteins and associated centromeric DNA that is responsible for mediating the segregation of sister chromatids to daughter cells via its interactions with the mitotic spindle. Continued identification of conserved kinetochore components in model systems such as yeast has provided a rich resource of candidate genes that may be mutated or misregulated in human cancers. Systematic mutational testing and transcriptional profiling of CIN candidate kinetochore genes should shed light on the kinetochore's role in tumorigenesis, and on the general role CIN plays in cancer development.