| Summary: | The definitive diagnosis of Cushing’s disease (CD) in the presence of pituitary microadenoma remains a continuous challenge. Novel available pituitary imaging techniques are emerging. This study aimed to provide a structured analysis of the diagnostic accuracy as well as the clinical use of molecular imaging in patients with ACTH-dependent Cushing’s syndrome (CS). We also discuss the role of multidisciplinary counseling in decision making. Additionally, we propose a complementary diagnostic algorithm for both de novo and recurrent or persistent CD. A structured literature search was conducted and two illustrative CD cases discussed at our Pituitary Center are presented. A total of 14 CD (<i>n</i> = 201) and 30 ectopic CS (<i>n</i> = 301) articles were included. MRI was negative or inconclusive in a quarter of CD patients. <sup>11</sup>C-Met showed higher pituitary adenoma detection than <sup>18</sup>F-FDG PET–CT (87% versus 49%). Up to 100% detection rates were found for <sup>18</sup>F-FET, <sup>68</sup>Ga-DOTA-TATE, and <sup>68</sup>Ga-DOTA-CRH, but were based on single studies. The use of molecular imaging modalities in the detection of pituitary microadenoma in ACTH-dependent CS is of added and complementary value, serving as one of the available tools in the diagnostic work-up. In selected CD cases, it seems justified to even refrain from IPSS.
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