Most solid tumors are unable to maintain the stability of their genomes at the chromosome level. Indeed, cancer cells display highly rearranged karyotypes containing translocations, amplifications, deletions, and gains and losses of whole chromosomes, which reshuffle steadily. This chromosomal instability most likely occurs early in the development of cancer, and may represent an important step in promoting the multiple genetic changes required for the initiation and/or progression of the disease. Different mechanisms may underlie chromosome instability in cancer cells, but a prominent role for telomeres, the tip of linear chromosomes, has been determined. Telomeres are ribonucleoprotein structures that prevent natural chromosome ends being recognized as DNA double-strand breaks, by adopting a loop structure. Loss of telomere function appears from either alteration on telomere-binding proteins or from the progressive telomere shortening that normally occurs under physiological conditions in the majority of cells in tissues. Importantly, unmasked telomeres may either trigger the senescent phenotype that has been linked to the aging process or may initiate the chromosome instability needed for cancer development, depending on the integrity of the DNA damage checkpoint responses. Telomere dysfunction contributes to chromosome instability through end-to-end chromosome fusions entering breakage-fusion-bridge (BFB) cycles. Resolution of chromatin bridge intermediates is likely to contribute greatly to the generation of segmental chromosome amplification events, unbalanced chromosome rearrangements, and whole chromosome aneuploidy. Noteworthy is the fact that telomere length heterogeneity among individuals may directly influence the scrambling of the genome at tumor initiation. However, reiterated BFB cycles would randomly reorganize the cell karyotype, thus increasing the genetic diversity that characterizes tumor cells. Even though a direct link is still lacking, multiple evidence lead one to believe that telomere dysfunction directly contributes to cancer development in humans. The expansion of highly unstable cells due to telomere dysfunction enhances the genetic diversity needed to fuel specific mutations that may promote cell immortalization and the acquisition of a tumor phenotype.