The serine proteases of T lymphocytes provide immunity to infection. Serine Proteases Inhibitors (serpins) control the recognition of antigen, effector function, and homeostatic control of T lymphocytes through the inhibition of serine protease targets. Serpins are important promoters of cellular viability through their inhibition of executioner proteases, which affects the survival and development of long-lived memory T cells. The potent antiapoptotic properties of serpins can also work against cellular immunity by protecting viruses and tumors from eradication by T lymphocytes. Recent insights from knockout mouse models demonstrate that serpins also are required for hematological progenitor cells and so are critical for the development of lineages other than T lymphocytes. Given the emerging role of serpins in multiple aspects of lymphocyte immunity and blood development, there is much potential for new therapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets.