Analysis of X-ray data concerning 277 estranes, androstanes, and pregnanes and comparison with progesterone receptor binding data have prompted the following observations. In general: 1. The flexibility of natural steroid hormones permits them to take up conformations optimal for binding to sites on proteins that vary in individual structural requirements. 2. When substituents strain the fused ring system, the strain will be delocalized and often transmitted to the most flexible point of the molecule, thus giving rise to conformational transmission effects. Consequently, substituents will generally stabilize a specific conformation, limiting protein interaction and enhancing a specific hormone response. 3. Hydrogen bond patterns in crystals can be used to predict points of active site attachment. 4. Distortions resulting from crystal packing forms are insignificant. Progestin receptor binding affinity: 5. Complementarity of fit is not specific on the alpha and beta faces of the B, C, and D rings. 6. The delta4-3-one composition is the only consistently required element. 7. Five of the eight highest-affinity binders have inverted A rings. Others may be easily converted to it. 8. The inverted A ring is proposed as the optimal conformation and primary factor controlling binding. 9. An A ring binding pattern is apparent in other steroidal hormones. 10. The D-ring region is open to contribute to conformational change in the receptor or genome interaction.