Abstract Kinetochores are large protein structures assembled on centromeric DNA during mitosis that bind to microtubules of the mitotic spindle to orchestrate and power chromosome movements. Deregulation of kinetochore–microtubule (KT–MT) attachments has been implicated in driving chromosome instability and cancer evolution; however, the nature and source of KT–MT attachment defects in cancer cells remain largely unknown. Here, we highlight recent findings suggesting that oncogene-driven changes in kinetochore regulation occur in glioblastoma multiforme (GBM) and possibly other cancers exhibiting chromosome instability, giving rise to novel therapeutic opportunities. In particular, we consider the GLE2p-binding sequence domains of BubR1 and the newly discovered BuGZ, two kinetochore-associated proteins, as candidate therapeutic targets for GBM. Clin Cancer Res; 21(2); 233–9. ©2014 AACR.