Chromosomal instability (CIN) is a common cause of tumour heterogeneity and poor prognosis in solid tumours and describes cell–cell variation in chromosome structure or number across a tumour population. In this article we consider evidence suggesting that CIN may be targeted and may influence response to distinct chemotherapy regimens, using HER2-positive breast cancer as an example. Pre-clinical models have indicated a role for HER2 signalling in initiating CIN and defective cell-cycle control, and evidence suggests that HER2-targeting may attenuate this process. Anthracyclines and platinum agents may target tumours with distinct patterns of karyotypic complexity, whereas taxanes may have preferential activity in tumours with relative chromosomal stability. A greater understanding of karyotypic complexity and identification of methods to directly examine and target CIN may support novel strategies to improve outcome in cancer. J. Cell. Biochem. 111: 782–790, 2010. © 2010 Wiley-Liss, Inc.