In this paper three concepts will be briefly discussed. The first of these is optimization of antagonist design; the second is the phenomenon of side-effects via cross-over into receptors for other classes of steroid hormones; the third is the possibility that naturally-occurring steroids may act as physiological antagonists in certain effector systems. To illustrate these concepts three areas of current work will be discussed. (i) 18-Deoxyaldosterone has a high affinity for mineralocorticoid receptors, a low affinity for androgen receptors (AR), is converted biosynthetically to aldosterone, and is a partial agonist/predominant antagonist in rat and toad mineralocorticoid test systems. The features of such an antagonist (specificity, biosynthetic incorporation rather than blockade, residual agonist activity) will be compared with currently available anti-mineralocorticoids. 1. (ii) A variety of drugs (chlorpromazine, aldactone, cimetidine) occupy AR, but have negligible affinity (<0.001%) for oestrogen receptors (ER). For such drugs, the mechanism of their “oestrogenic/anti-androgenic” side-effects (e.g. gynaecomastia, elevation of testosterone-oestradiol binding globulin-TeBG) would appear then to be anti-androgenic. In addition to occupying ER, oestradiol and diethylstilboestrol (DES) have non-negligible affinities for AR. Accordingly, under some pathophysiological conditions (high dose oestrogens for carcinoma of breast or prostate), or perhaps even physiologically (e.g. pregnancy), certain effects of oestrogens may be a reflection of anti-androgen activity via AR occupancy, rather than necessarily a primary ER mediated event. 2. (iii) The adrenal has a portal vascular system, so that ambient steroid concentrations in the adrenal medulla are far higher than elsewhere. We have recently described a class of binding sites with novel specificity, dexamethasone (DM) > 17α-hydroxyprogesterone (17α-OHP) > Cortisol (F) > triamcinolone acetonide (TA), in a variety of bovine tissues, including adrenal medulla. These sites have an affinity for 17α-OHP < 10 −8 M, and have been demonstrated not to be classical glucocorticoid receptors. While a receptor role for such sites awaits proof, they fulfil all the criteria examined to date for physiological receptors. In adrenal medulla, and other tissues under some circumstances, such sites would appear to be always filled, presumably predominantly by 17α-OHP and F. If such sites function as 17α-OHP receptors in adrenal medulla, then a physiological antagonist role for F would appear necessary to modulate agonist occupancy by 17α-OHP.