The best and most economic treatment for melanoma is achieved through technologies that offer an early and precise diagnosis. Dermoscopy is more accurate than naked eye but is limited by high rates of unnecessary excisions for histopathological confirmation. Depending on dermoscopy specialization, 5 to 30 benign lesions must be excised to detect a melanoma. Digital dermoscopy follow-up (DDF) improves the rate of melanoma diagnosis to 7% during monitoring, but still demands for better alternative technologies. The introduction of Reflectance Confocal Microscopy (RCM) enables in vivo lesion examination with higher diagnostic accuracy and specificity, particularly for equivocal lesions. However, so far, RCM clinical studies have been mainly limited to hypothetical estimates of clinical application in a small patient population and have not intended to influence clinical patient pathways. Moreover, these studies were retrospective and did not fully consider undiagnosed malignant lesions and patients’ preference for biopsy.