Serine Proteases control a wide variety of physiological and pathological processes in multi-cellular organisms, including blood clotting, cancer, cell death, osmo-regulation, tissue re-modeling and immunity to infection. T lymphocytes are required for adaptive cell mediated immunity and serine proteases are not only important for effector function but also for homeostatic regulation of cell numbers. Serine Proteases Inhibitors (Serpins) are the physiological regulators of serine proteases activity. In this review, I will discuss the role of serpins in controlling the recognition of antigen, effector function and homeostatic control of T lymphocytes through the inhibition of physiological serine protease targets. An emerging view of serpins is that they are important promoters of cellular viability through the inhibition of executioner proteases. This will be discussed in the context of the T lymphocyte survival during effector responses and the development and persistence of long-lived memory T cells. The potent anti-apoptotic properties of serpins can also work against adaptive cellular immunity by protecting viruses and tumors from eradication by cytotoxic T cells (CTL). Given the important role serpins play in T lymphocyte immunity, I will review the progress to date in developing new immunotherapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets.