Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6–7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors. Display omitted •X-Ray structures of MR and GR reveal a conserved plasticity near helices 6 and 7•Ligand binding simulations provide a functional role to the observed plasticity•Residence time measurements correlate with the proposed binding mechanism•Differences in receptor blueprints promote differential evolutionary constraints Edman et al. combined X-ray crystallography, computational simulations, and residence time measurements to uncover the ligand entry and exit processes of steroid hormone receptors. Subsequent bioinformatics analyses confirmed that differences in the details of the ligand entry mechanism lead to differential selection pressure across the receptor family.