Our study aims to characterize molecular heterogeneity in sMTC in order to identify pathways that may improve patient's stratification and support more personalized clinical management strategies.<h4>Methods</h4>Deep targeted next-generation sequencing of 31 neuroendocrine- and cancer-related genes was performed on tumor samples from 94 patients with sMTC to characterize the somatic mutational landscape beyond canonical drivers.<h4>Results</h4><i>RET</i> and <i>RAS</i> mutations were detected in 53% and 29% of cases, respectively, while 18% of tumors lacked both alterations. Here, RET is linked to cancer.