<p>Cushing’s Syndrome represents a paradigmatic clinical model of circadian disruption secondary to chronic hypercortisolism. Under physiological conditions, glucocorticoid secretion follows a robust circadian rhythm coordinated by a central clock in the suprachiasmatic nucleus and peripheral oscillators in virtually all tissues. This molecular clock network, governed by feedback loops involving CLOCK, BMAL1, PER, and CRY genes, is severely disrupted in Cushing’s Syndrome, although this aspect remains underexplored. Recent studies have highlighted that endogenous hypercortisolism leads to a loss of rhythmic expression of clock genes and alters immune cell oscillations, which only partially recover after remission. This persistent desynchronisation may contribute to the sustained morbidity and elevated mortality observed in these patients even after normalisation of cortisol levels. Emerging evidence from clinical trials suggests that tailored circadian therapies using steroidogenesis inhibitors such as metyrapone and osilodrostat – administered in alignment with the natural cortisol rhythm – can restore salivary cortisol profiles, improve inflammatory markers, and enhance quality of life and sleep. Despite promising results, circadian-targeted treatment remains an unmet need in current clinical practice. Restoring circadian integrity in Cushing’s Syndrome may offer a novel therapeutic way to improve long-term outcomes by addressing the systemic dysregulation driven by chronic cortisol excess.</p>