The immune system protects organisms from pathogens. The immune cells, in particular T- and B-lymphocytes, develop and acquire effector functions in specialized tissues called the lymphoid organs. The lymphoid organs exhibit lower oxygen tensions than the blood or the atmosphere. Furthermore, inflammatory and tumor environments where lymphocytes execute effector functions also have very low oxygen tensions. These findings led to the hypothesis that lymphocytes may have evolved adaptive mechanisms to function under hypoxic conditions. Cellular responses to hypoxia are triggered by the hypoxia inducible factor-1α (HIF-1α). In this paper we review the development and function of T- and B-lymphocytes in the absence HIF-1a. Our studies suggest that HIF-1α deficiency depresses the function of cytotoxic T-lymphocytes and blocks B-cell development in the bone marrow. B1 lymphocytes of fetal origin, on the other hand, accumulate and may produce auto-antibodies and autoimmunity.