Many different cellular processes are altered by microenvironmental changes in the oxygen level, particularly hypoxia. In most cases, these hypoxic effects are mediated via alterations in cellular signal transduction pathways. Low oxygen states are generally viewed as deleterious; however, recent studies show that alterations in oxygen levels are physiologically important, influencing cells in a variety of ways. Low oxygen levels can stimulate cellular processes, such as the production of tumor necrosis factor, interleukin (IL)-1, IL-8, and nuclear factor kappa B. Kupffer cell-mediated alterations in cocultured hepatocyte function are altered by pre-exposure to hypoxic culture conditions, whereas superoxide production, intracellular pH, and adenosine triphosphate levels are decreased by hypoxia. Hypoxia followed by reoxygenation stimulates tyrosine kinase enzymes and increases intracellular calcium in a variety of cells. This review highlights recent findings concerning the manner and mechanisms by which low oxygen levels influence cell functions and cellular signaling systems. Detailed information is still lacking about the location and mechanism of most hypoxic-mediated alterations in cell signaling pathways. However, information about how factors altered by trauma and sepsis, such as Po2, acidosis, and endotoxin, effect cellular signaling pathways is rapidly emerging. Understanding the mechanism by which oxygen availability alters cell function will be important to the development of optimal therapies for post-traumatic shock and organ dysfunction.