The purpose of this review is to give a comprehensive understanding about the anti-inflammatory steroidal antedrugs. The concept of antedrug first came into light in 1982 and since then a few academic institutions and some pharmaceutical industries worldwide are performing active research in this avenue in search of safer therapeutic agents. Although the concept primarily focused to the discovery of safer topical anti-inflammatory steroids, the scopes has broadened involving other therapeutic drug classes as well. A recent review has outlined briefly on all different currently available approaches of antedrug discovery. Because of the increasing interests on antedrug approach and vastness of steroid chemistry, the focuses of the present review had been concentrated on anti-inflammatory steroidal antedrugs. The research efforts since 1980s in the chemical synthesis and pharmacological actions of the steroidal antedrugs have dictated the breadth of this article. For the sake of the completeness of information and consistency, historical materials and references to earlier relevant works has also been cited. After a brief introduction about the glucocorticoid therapy, especially their clinical applications and deleterious shortcomings and earlier medicinal chemical efforts to overcome those shortcomings, the antedrug approach is introduced outlining the rationale, scopes and successes. Borderline between the other related concepts such as prodrug has also been explained. The synthetic approaches of all chemical classes of anti-inflammatory steroidal antedrugs and their pharmacological activities have been the main emphasis and a section on pro-antedrugs has also been devoted. Finally, to reflect the scopes and future of the concept of antedrug, drugs in clinical use or in pipeline that are developed based on this concept has been placed before the concluding remarks. 1.1. An Introduction to Glucocorticoid Therapy The beneficial effects of glucocorticoids in the treatment of chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune disorders have been appreciated for over 50 years but not without serious complications, which have imposed limitations on the clinical use of this class of drugs.1,2 Suppression on the hypothalamic-pituitary-adrenal (HPA) axis, the immune system, aggravation of diabetes, hypertension, osteoporosis, and retardation of growth in children are few of the most deleterious side effect.3–7 A considerable research effort has been devoted to the structural modifications of glucocorticoids, with a hope of increasing their potencies while minimizing their propensity to elicit systemic adverse effects, and some success had been evident in producing potent glucocorticoids with minimum salt-retaining activity.8–11 The introduction of fluorine at the 9α-position of the natural hydrocortisone (1) increased the binding affinity to glucocorticoid (GC) receptors and retarded the oxidation of the proximal 11-OH group, e.g., fludrocortisone (2). The introduction of 1-double bond, as in prednisolone (3) led to increased potency with reduced salt retaining activity. The incorporation of C6α-methyl, to prevent hydroxylation at this position as in 6α-methylprednisolone (4), increased both potency and duration of action. The incorporation of 16-methyl, in addition to the 9α-flouro and Δ1-double bond, resulted increase in anti-inflammatory potency by about 25 folds, e.g., dexamethasone (6) and betamethasone (7). The main challenge or shortcomings with GC therapy, however, has been in the separation of anti-inflammatory effects on target tissues or organs from systemic glucocorticoid effects, which are largely inherent in the nature of steroids themselves. Not only do they possess multiple biological activities, but structural requirements for various activities seem to be overlapping and inseparable.1–5 Furthermore, GC receptors are present in virtually all tissues, and these receptors appear to be similar or identical on the basis of the relative affinities of GC ligands for these receptors. The introduction of C16,C17-acetonides12 and esterification at C17- and/or C21-OH groups that increased lipophilicity of glucocorticoids proved to be useful for topical application.13,14 Other changes more significant from the chemistry viewpoint rather than pharmacotherapeutic viewpoint included the replacement of C21- and C11-OH with chlorine, incorporation of fused phenylpyrazole ring at C2 and C3 or fused oxazole ring at C16 and C17.15,16 The relatively newer potent anti-inflammatory agents like flurandrenolone (8), fluorometholone (9), and flucinolone (10) are used only topically for the treatment of psoriasis due to their systemic toxicities.