Abnormal chromosome content known as aneuploidy is the most common characteristic of human solid tumours. The molecular roots of aneuploidy lie in defective centromere/kinetochore assembly and function leading to improper chromosome segregation. These defects can be caused by mutations and/or by altered expression of diverse kinetochore proteins. In addition to proteins, non-coding RNA deriving from centromeric repeats plays an active role, mostly through the RNAi pathway, in the formation of pericentromeric and centromeric heterochromatin, both of them important for proper centromere function. We propose that stoichiometric expression of major kinetochore components such as non-coding centromeric RNA and proteins is crucial for centromere/kinetochore assembly and function. Slight changes in expression of non-coding RNA or mutations in the RNA metabolic pathways induce chromosome instability, mis-segregation and aneuploidy, facilitating finally tumourigenesis.