Glucocorticoid (GC) usage is the most common non-traumatic cause of osteonecrosis of the femoral head (ON). Despite the strong association of GC with ON, the underlying mechanisms have been unclear. Investigators have proposed both direct and indirect effects of GC on cells. Indirect and direct mechanisms remain intimately related and often result in positive feedback loops to potentiate the disease processes. However, the direct effects, in particular apoptosis, have recently been shown to be increasingly important. Suppression of osteoblast and osteoclast precursor production, increased apoptosis of osteoblasts and osteocytes, prolongation of the lifespan of osteoclasts and apoptosis of endothelial cells (EC) are all direct effects of GC usage. Elevated blood pressure through several pathways may raise the risk of clot formation. High-dose GC also decreases tissue plasminogen activator activity (t-PA) and increases plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels increasing the procoagulant potential of GC. Inhibited angiogenesis, altered bone repair and nitric oxide metabolism can also result. Also, GC treatment modulates other vasoactive mediators such as endothelin-1, noradrenalin and bradykinin. Thus, GCs act as a regulator of local blood flow by modulating vascular responsiveness to vasoactive substances. Vasoconstriction induced in intraosseous femoral head arteries causes femoral head ischemia. GCs also cause ischemia through increased intraosseous pressure, which subsequently decreases the blood flow to the femoral head by apoptosis of ECs as well as elevating the level of adipogenesis and fat hypertrophy in the bone marrow. It is difficult to predict which patients receiving a specific dose of GC will develop ON, indicating individual differences in steroid sensitivity and the potential of additional mechanisms. The textbook model of ON is a multiple hit theory in which, with a greater number of risk factors, the risk of ON increases. While more effort is needed to better comprehend the role of GC in ON, newer data on GC action upon the endothelial cell and the regional endothelial bed dysfunction theory sheds new light on particular GC mechanisms. Better understanding of GC pathomechanisms can lead to better treatment options.