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The highly phosphorylated glycoprotein Osteopontin (OPN) is a multifaceted protein with a diversity of roles in many immunological processes, and has recently been found to have a significant role in the Hypothalamus-Pituitary-Adrenal (HPA) axis. Its role was discovered when unstressed OPN-knockout mice were found to have abnormally high basal corticosterone levels, which is the hormone typically elevated following stress induction of the HPA axis. Another protein rigorously studied and repeatedly identified in the successful functioning of the HPA axis is Leukemia Inhibitory Factor (LIF). I propose that OPN may possess a regulatory role in the expression of LIF, with the absence of OPN leading to a greater abundance of LIF mRNA, and consequently, over-production of corticosterone in non-stressful situations. Using the mouse anterior pituitary cell-line AtT-20, a common and highly useful model in HPA axis research, I have found evidence that treatment of these cells with OPN partially inhibits the expression of LIF mRNA. The dose-dependency of this inhibition appears to behave as either positive or negative depending on the cellular density of the culture treated with OPN. Should OPN turn out to be a regulator of LIF mRNA expression, then absence of OPN may lead to an over-abundance of LIF, therefore affecting the expression of several proteins downstream of LIF that potently stimulate corticosterone production, such as the cholesterol transport protein StAR. It may turn out that OPN has an especially significant and indispensable role in the HPA axis via regulation of LIF mRNA levels.