Part I, Chapter 3 of the Handbook was dedicated to the complementary function of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling pathways that need to operate in balance for effective stress coping, adaptation, and circadian organization. This chapter focuses on the therapeutic application of MR:GR ligands and modulators for (1) substitution therapy of adrenal-deficient patients which requires to mimic episodic secretions of the endogenous glucocorticoids, (2) pharmacotherapy to treat symptoms of, for example, inflammatory and autoimmune disorders, with synthetic glucocorticoids that may have severe psychiatric side effects, and (3) diagnostic purpose as well as drug target for treatment of neuropsychiatric disorders. The chapter is concluded with perspectives toward novel modulators that target coregulators of MR and GR with greater selectivity, enhanced efficacy, and reduced side effects.