CD8+ T cells respond to antigen stimulation through a process of activation, division, and differentiation generating a large pool of activated effector cytolytic T lymphocytes (CTLs). Many cancer patients harbor the accordant precursor CTLs capable of responding to various tumor‐associated antigens (TAA). In selected cases, vaccination with these TAA can elicit detectable antitumor responses. Presently, the clinical outcome of cancer vaccination remains inadequate. The lack of clinical efficacy may be attributed to various molecular and cellular mechanisms developed by tumors to successfully evade the host immune system. Some of these mechanisms have been identified. It is becoming increasingly apparent that immunotherapy with the sole objective of inducing immune activation is in itself not sufficient to fully overcome the mechanisms averting efficient antitumor responses. Strategies to neutralize tumor‐induced immune suppression have to be developed in parallel to antigenic stimulation. Our data show that both oxidative stress‐ and antigen‐mediated preferential cell death of antigen‐experienced memory CTLs may be a major contributor to tumor‐induced immune dysfunction. The persistence of functional CTLs is a key element for an efficient antitumor response and affects the outcome of any immunotherapy protocol. We therefore propose that protecting CTLs from premature death by identifying and targeting the responsible pathway can lead to substantial enhancement in antitumor response. In this review, we discuss some of the fundamental factors that may be involved in the modulation of the different lymphocyte subsets towards sensitization or resistance to tumor‐induced stress.