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Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies. Recently, however, additional consequences and associations with CIN have been revealed, prompting the need to understand this universal hallmark of cancer in a multifaceted context. This review is focused on the investigation of possible links between CIN, metastasis and the host immune system in cancer development and treatment. We specifically focus on these links since most cancer deaths are due to the consequences of metastasis, and immunotherapy is a rapidly expanding novel avenue of cancer therapy.