The mineralocorticoid receptor (MR) plays a central role in sodium homoeostasis by transducing the response to aldosterone in the distal nephron and other sodium transporting epithelia. The MR is a member of the nuclear receptor family of ligand-dependent transcription factors; it is unusual in being the receptor for two steroid hormones aldosterone and cortisol (which also binds to the closely related glucocorticoid receptor). Less well recognised is that progesterone also binds to the MR with high affinity. The conformation of the ligand-bound receptor is determined by the ligand including whether the conformation is agonist or antagonist. An agonist MR conformation then enables interactions with DNA, other MR (homodimerization) and coregulatory molecules to regulate gene expression. Insights into the structural determinants of an agonist response to ligand come from studies of the evolution of the MR. Progesterone is an agonist in the fish MR, but antagonist in the MR of terrestrial vertebrates; this switch results from the loss of a critical leucine that mediates a leucine:leucine interaction between helix 1 and helix 8 which enables the agonist response to progesterone. The insights into the intramolecular dynamics of activation suggest novel ways in which MR antagonism may be achieved beyond the current, progesterone-based antagonists in clinical use.