The development of resistance to glucocorticoids (GCs) in therapeutic regimens poses a major threat. Generally, GC resistance is congenital or acquired over time as a result of disease progression, prolonged GC treatment or, in some cases, both. Essentially, disruptions in the function and/or pool of the glucocorticoid receptor α (GRα) underlie this resistance. Many studies have detailed how alterations in GRα function lead to diminished GC sensitivity; however, the current review highlights the wealth of data concerning reductions in the GRα pool, mediated by disease-associated and treatment-associated effects, which contribute to a significant decrease in GC sensitivity. Additionally, the current understanding of the molecular mechanisms involved in driving reductions in the GRα pool is discussed. After highlighting the importance of maintaining the level of the GRα pool to combat GC resistance, we present current strategies and argue that future strategies to prevent GC resistance should involve biased ligands with a predisposition for reduced GR dimerization, a strategy originally proposed as the SEMOGRAM–SEDIGRAM concept to reduce the side-effect profile of GCs.