Septic syndromes still remain a major but largely under-recognized healthcare problem worldwide accounting for thousands of deaths every year. Despite numerous clinical trials, therapies have failed to mitigate the devastating effects of these conditions. It is now agreed that the initial hypotheses for sepsis pathophysiology have been misconstrued. Sepsis deeply perturbs immune homeostasis by concomitantly inducing a strong inflammatory response and a major anti-inflammatory process, acting as a negative feedback. Several lines of evidences indicate that this inhibitory response secondly may be deleterious in patients who survived initial resuscitation, as it may be directly responsible for worsening outcome by decreasing resistance to secondary nosocomial infections. In this context, while the majority of clinical and basic science conducted so far has focused on innate immune cell depressed functions (especially monocytes), the contribution of T lymphocyte anergy has been somewhat ignored. This review focuses on lymphocyte dysfunctions described so far in patients and on potential new therapeutic strategies aimed at restoring a functional lymphocytic response after sepsis.