Aneuploidy is one of the most frequent genetic alterations in solid tumors. It is commonly caused by cell division errors that are induced by oncogene activation or loss of tumor suppressor functions. In addition, certain viral oncoproteins have been implicated in the induction of chromosome copy number changes. Aneuploidy and inactivation of p53 frequently coincide in human cancers but there is increasing evidence that loss of p53 by itself is not a primary cause of aneuploidy. Nonetheless, p53 inactivation synergizes with additional oncogenic events to promote aneuploidy and may facilitate chromosomal imbalances through indirect mechanisms. This review summarizes the current knowledge about the association between aneuploidy and p53, and discusses two of the most controversial mechanisms that have been implicated in genomic instability associated with loss of p53: subversion of ploidy control and aberrant centrosome duplication. © 2005 Elsevier Inc. All rights reserved.