Immortalization achievement is a feature common to nearly all human cancers. In a simplistic concept, tumour cells in order to acquire an immortality phenotype require at some time to counteract telomere erosion that controls the number of divisions that cells are allowed. Knowledge on mechanisms leading to telomerase reactivation/re-expression was scarce although telomerase (TERT) activity is detected in up to 90% of cancers. Recently, telomerase promoter mutations (TERTp) were discovered and are, presently, one of the contributors for this process. Our group participated in the discovery of TERTp mutations and established this mutations as a prognostic biomarker in several human cancers. Our studies revealed that patients harbouring tumours with these mutations present a poorer prognosis, and ultimately, a lower disease-free survival and hold a higher disease-specific mortality. Additionally, we have been deciphering the biological mechanisms of the TERTp mutations in several human cancers.