Quantitative lymphocyte alterations are frequent in patients with cancer, and strongly impact prognosis and survival. The development of cancers in immunosuppressed patients has demonstrated the contribution of different T cell populations, including CD4 cells, in the control of cancer occurrence.Whereas absolute numbers of neutrophils, platelets and red blood cells are routinely monitored in clinic following treatments, because of possible short-term complications, absolute lymphocyte counts (ALC), their subpopulations or diversity (phenotype, TCR) are rarely analyzed and never used to choose therapy or as prognostic criteria. The recent identification of immune checkpoint inhibitors (ICPi) as powerful therapeutic agents has revitalized immunotherapy of cancer in a broader group of diseases than anticipated. The status of the immune system is now recognized as an important biomarker for response to these novel treatments. Blood ALC values, along with tumor infiltration by CD8T cells, and ICPi and ICPi-ligand expression, are likely to be a potential marker of sensitivity to anti-ICPi therapy.In this article, we review the current knowledge on the incidence and significance of lymphopenia in cancer patients, and discuss therapeutic strategies to restore lymphocyte numbers.