Most cancers progress with the accumulation of genetic mutations with time and this is frequently associated with the acquisition of genomic instability in the form of whole chromosome changes, chromosomal rearrangements, gene amplifications or smaller changes at the nucleotide level. Whole chromosome instability (W-CIN), characterised by aneuploidy, is a major form of genomic instability observed in human cancers and several lines of evidence now support the argument that W-CIN is a promoter of tumourigenesis rather than being a passenger event. The primary mechanism proposed for evolution of CIN is abnormalities in mitosis/cytokinesis. However, mutations in genes directly involved in controlling mitosis/cytokinesis are rare in human cancers and so the mechanisms underpinning the evolution of CIN in cancers are not currently clear. On the other hand, mutations in RAS or BRAF are frequently found in human cancers, many of which demonstrate CIN, suggesting a possible link between deregulated signaling through the RAS/RAF/MEK/ERK pathway and CIN. In this review, we focus on a potential relationship between deregulated RAS/RAF signaling and CIN, and discuss possible mechanisms connecting the two.