The cellular response to aldosterone is mediated by the mineralocorticoid receptor (MR). This response is best characterized in the renal epithelia with control of sodium and water homeostasis. However, the MR binds more than one ligand and has wide tissue distribution with multiple roles in cardiovascular function, immune cell signaling, neuronal fate and adipocyte differentiation. This chapter will provide a review of MR structure and function, and an analysis of the critical interactions involved in MR-mediated signal transduction, which contribute to ligand- and tissue-specificity. MR signal-transduction can be best viewed as a series of interactions, the first being the binding of ligand which confers a ligand-specific conformation upon the receptor. This conformation then determines subsequent interactions with different domains of the receptor, chromatin, coregulators and other transcription factors. Understanding the relevant mechanisms for selective MR signaling in terms of these interactions opens the possibility of novel therapeutic approaches for the treatment of MR-mediated diseases.