Shelterin is a highly conserved chromosome end-capping complex, which encompasses TRF1, TRF2, TPP1, POT1, TIN2 and RAP1. Although extensive cell culture studies suggest that shelterin is essential for telomere regulation, its role in telomere biology and disease in the context of the organism remained elusive due to lack of viable loss-of-function mouse models. I will first report here on mice and cells conditionally deleted for TRF1, TPP1 and RAP1. Absence of TRF1 and TPP1 results in perinatal mortality, severe skin atrophy and hyperpigmentation, and widespread epithelial dysplasia, which are associated to induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. Abrogation of the p53 and RB pathways in Trf1 and Tpp1-deleted mouse embryonic fibroblasts (MEF) bypasses senescence but results in widespread chromosomal instability concomitant with activation of the ATM/ATR DNA damage signalling pathways and phosphorylation of the downstream kinases Chk1 and Chk2. In vivo, p53 deficiency ameliorates mouse survival and leads to development of malignant squamous cell carcinomas in the skin of Trf1 and Tpp1 deficient mice, demonstrating a tumor suppressor activity of shelterin components. Finally, we show that the levels of some shelterin components decrease during physiological organismal aging. Together, these results show that dysfunction of telomere-associated proteins is sufficient to produce severe telomeric damage and loss of telomere capping in the absence of telomere shortening, resulting into premature tissue degeneration, acquisition of chromosomal aberrations and neoplastic lesions.