Meaningful answers to the question of the relationship between glucocorticoid structure and activity have emerged. Structural change has predictable effects on susceptibility to the action of metabolizing enzymes, on receptor affinity, and on intrinsic activity. These effects are, in principle, amenable to mathematical modeling techniques. The fascinating possibility of being able to calculate receptor affinity directly from chemical structure has already been realized through the development of an equation [19] that allows the calculation of receptor binding of any glucocorticoid from structural parameters. Utilizing knowledge of the free energy contributions of the substituents and the hydrophobicity and A-ring conformation of the steroids, receptor affinity for a large number of compounds could be described in terms of four parameters. A general relationship was derived relating the equilibrium dissociation constant to a surface area term, a polar interaction term, and A-ring tilt term, and a size limitation function for the 9 alpha-substituent. The excellent correlation obtained suggests that these four factors are the major determinants of glucocorticoid receptor interactions. It is clear that the use of a mathematical relationship that defines the strength of steroid-receptor interaction is a valuable tool for investigating structure-activity relationships. This would be especially true in the design of steroid drugs. The use of a linear free-energy equation is superior to the assumption of substituent additivity in predicting binding affinities. This type of relationship will be useful in the preparation of steroids for use in affinity labeling studies and should be adaptable to other binding systems in which it is desirable to obtain synthetic analogs for more potent activity or specificity.