Alteration of the epigenome is associated with a wide range of human diseases. Therefore, deciphering the pathways that regulate the epigenetic modulation of gene expression is a major milestone for the understanding of diverse biological mechanisms and subsequently human pathologies. Although often evoked, little is known on the implication of telomeric position effect, a silencing mechanism combining telomere architecture and classical heterochromatin features, in human cells. Nevertheless, this particular silencing mechanism has been investigated in different organisms and several ingredients are likely conserved during evolution. Subtelomeres are highly dynamic regions near the end of the chromosomes that are prone to recombination and may buffer or facilitate the spreading of silencing that emanates from the telomere. Therefore, the composition and integrity of these regions also concur to the propensity of telomeres to regulate the expression, replication and recombination of adjacent regions. Here we describe the similarities and disparities that exist among the different species at chromosome ends with regard to telomeric silencing regulation with a special accent on its implication in numerous human pathologies.