Glucocorticoids are widely used as anti-inflammatory agents, however, their use is limited by side effects. A long-term goal of pharmaceutical research has been the development of an agent that will mimic the anti-inflammatory actions of glucocorticoids without the undesirable side effects. This article reviews the diverse pharmacological approaches used to identify likely glucocorticoid substitutes and compares successful and unsuccessful approaches. All anti-inflammatory drugs that demonstrate clinical utility share an ability to modulate lymphocyte function. Given that glucocorticoids are also potent inhibitors of lymphocyte function, this property may be essential for clinically useful anti-inflammatory activity.