Immortalization is an indispensable step in oncogenesis. Most of the human malignant cells attain their immortality through stabilization of their telomere length by reactivating telomerase enzyme, a specialized reverse transcriptase. I presented in my thesis two promising approaches to target telomerase in immortal human cell lines using combinational strategies. We designed an oligonucleotide family, composed of a 13mer antisense sequence against the hTR template part and a 3' or 5' (s4dU)n moiety, possibly interacting with the catalytic protein subunit of human telomerase (hTERT), and characterized the in vitro inhibition parameters of the members. The potent and specific derivate (s4dU)8AS(PS), selected for cell culture studies could enter human cells, and caused, after a long-term treatment, death of the entire treated immortal cell population. We proved that all-trans-retinoic acid (ATRA) and arsenic trioxide (As2O3) cooperate to downregulate hTERT expression in both retinoid sensitive and resistant cell lines. hTERT repression results in a decrease of telomerase activity and leads to telomere shortening and subsequent cell death. This synergistic effect of ATRA and As2O3 could not be exclusively explained by chromatin modifications and the mechanisms of hTERT repression remain to be elucidated. Nevertheless, our findings provide direct evidence that telomerase targeting can represent a likely new mechanism by which ATRA/As2O3 therapy can exert its action in acute promyelocytic leukemia patients.