<p>Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signature and molecular behaviour of human telomeric chromatin. Recent structural and genetic studies further highlight the distinctive and dynamic nature of the telomeric architecture. Here we present an updated perspective on telomeric chromatin, focusing on the unique features that set telomeres apart from other genomic regions and that equip them to address the specific challenges at chromosome ends. In addition, we discuss how alterations in telomeric chromatin influence stem cells, inherited diseases and cancer, demonstrating how telomere architecture governs both its integrity and function.</p>