Telomere maintenance and telomerase reactivation is essential for the transformation of most human cancer cells. Telomere shortening to the threshold length, mutations of the telomere-associated proteins, and/or telomerase RNA lead to telomeric dysfunction and therefore genomic instability. Telomerase up-regulation in 85% of human cancer cells has become a hallmark of cancers, hence a promising target for anticancer therapy. In this review, we discuss the mechanism of cancer due to telomere dysfunction and the resulting biological effects, the control of telomerase activity, and the new developments in cancer therapies targeting telomere and telomerase.