Cushing's disease (CD) is a rare disabling condition caused by 
Adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary. The 
majority of corticotropic adenomas are monoclonal and occur sporadically. Only 
rarely does CD arise in the context of genetic familial syndromes. Targeted 
sequencing of oncogenes and tumour suppressor genes commonly mutated in other 
tumours did not identify recurrent mutations. In contrast, next generation 
sequencing allowed us recently to clarify the genetic basis of CD: we identified 
somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene in a 
significant portion of corticotropinomas. These mutations represent a novel and 
unique mechanism leading to ACTH excess. Inhibition of USP8 or its downstream 
signalling pathways could represent a new therapeutic approach for the 
management of CD. In this review, we will focus on this new evidence and its 
implication for clinical care of affected patients.