The Endocrine Society has developed clinical practice guidelines for treating Cushing's syndrome (CS), a condition characterized by pathological hypercortisolism. The guidelines aim to reduce mortality and associated comorbidities by normalizing cortisol levels and treating comorbidities. The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to assess the strength of recommendations and the quality of evidence. The guidelines recommend initial treatment options, including surgical resection of primary lesions, and provide detailed advice on adjunctive management, remission and recurrence, glucocorticoid replacement, and second-line therapies. Key recommendations include: 1. **Treatment Goals**: Normalizing cortisol levels or action at its receptors to eliminate signs and symptoms of CS and treating comorbidities. 2. **Optimal Adjunctive Management**: Providing education, monitoring, and adjunctive treatment for comorbidities, and forming multidisciplinary teams. 3. **First-Line Treatment Options**: Initial resection of primary lesions, including unilateral adrenalectomy, transsphenoidal selective adenectomy, and bilateral adrenalectomy. 4. **Remission and Recurrence**: Individualized management based on postoperative cortisol levels, additional treatments for persistent hypercortisolism, and screening for recurrence. 5. **Glucocorticoid Replacement**: Glucocorticoid replacement for hypocortisolemic patients and follow-up tests to assess HPA axis recovery. 6. **Second-Line Therapeutic Options**: Shared decision-making for repeat transsphenoidal surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. The guidelines emphasize the importance of early diagnosis and treatment to improve outcomes and reduce mortality in CS patients.The Endocrine Society has developed clinical practice guidelines for treating Cushing's syndrome (CS), a condition characterized by pathological hypercortisolism. The guidelines aim to reduce mortality and associated comorbidities by normalizing cortisol levels and treating comorbidities. The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to assess the strength of recommendations and the quality of evidence. The guidelines recommend initial treatment options, including surgical resection of primary lesions, and provide detailed advice on adjunctive management, remission and recurrence, glucocorticoid replacement, and second-line therapies. Key recommendations include: 1. **Treatment Goals**: Normalizing cortisol levels or action at its receptors to eliminate signs and symptoms of CS and treating comorbidities. 2. **Optimal Adjunctive Management**: Providing education, monitoring, and adjunctive treatment for comorbidities, and forming multidisciplinary teams. 3. **First-Line Treatment Options**: Initial resection of primary lesions, including unilateral adrenalectomy, transsphenoidal selective adenectomy, and bilateral adrenalectomy. 4. **Remission and Recurrence**: Individualized management based on postoperative cortisol levels, additional treatments for persistent hypercortisolism, and screening for recurrence. 5. **Glucocorticoid Replacement**: Glucocorticoid replacement for hypocortisolemic patients and follow-up tests to assess HPA axis recovery. 6. **Second-Line Therapeutic Options**: Shared decision-making for repeat transsphenoidal surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. The guidelines emphasize the importance of early diagnosis and treatment to improve outcomes and reduce mortality in CS patients.