Tumoral transformation results from the loss of regulatory mechanisms that control normal cell growth. This regulation is given by a delicate balance between cell proliferation, differentiation and apoptosis. We have previously described that sublines derived from the T-cell leukemia Jurkat, and characterized by a highly proliferative phenotype, were resistant to Fas- and doxorubicin-induced apoptosis and to activation-induced cell death (AICD). In this review we will summarize the actual results of the characterization of these cell lines, mainly focused on: i) the mechanisms involved in the loss of expression of Fas and other functionally relevant surface proteins such as CD3, CD2, and CD59, revealing important defects in the secretory pathway with the complete lack of expression of endophilin-1 and CtBP/BARS, key enzymes in vesicle fission regulation; and ii) on the existence of a caspase-independent mitochondrial pathway involving the apoptosis-inducing factor (AIF) responsible for the delayed doxorubicin-induced apoptosis in Jurkat cell derived sublines.