The processes regulating telomere function have major impacts on fundamental issues in human cancer biology. First, active telomere maintenance is almost always required for full oncogenic transformation of human cells, through cellular immortalization by endowment of an infinite replicative potential. Second, the attrition that telomeres undergo upon replication is responsible for the finite replicative life span of cells in culture, a process called senescence, which is of paramount importance for tumor suppression in vivo. The process of telomere-based senescence is intimately coupled to the induction of a DNA damage response emanating from telomeres, which can be elicited by both the ATM and ATR dependent pathways. At telomeres, the shelterin complex is constituted by a group of six proteins which assembles quantitatively along the telomere tract, and imparts both telomere maintenance and telomere protection. Shelterin is known to regulate the action of telomerase, and to prevent inappropriate DNA damage responses at chromosome ends, mostly through inhibition of ATM and ATR. The roles of shelterin have increasingly been associated with transient interactions with downstream factors that are not associated quantitatively or stably with telomeres. Here, some of the important known interactions between shelterin and these associated factors and their interplay to mediate telomere functions are reviewed.