<b><i>Introduction:</i></b> Liquid biopsy is an innovative and efficient method for studying circulating tumor DNA. In conjunction with innovative techniques such as next-generation sequencing, it can provide real-time information on prognostic and predictive factors. <b><i>Case Presentation:</i></b> We report a case of advanced, unresectable medullary thyroid carcinoma with various rearranged during transfection (<i>RET</i>) and Kirsten rat sarcoma viral (<i>KRAS</i>) mutations in both blood liquid and tissue biopsies. After the initial failure of treatment with a tyrosine kinase inhibitor (TKI), a liquid biopsy analyzed by next-generation sequencing showed the presence of six different <i>RET</i> mutations and <i>KRAS</i>. Tissue biopsy also revealed two <i>RET</i> mutations. Due to these biopsy findings, the treatment was changed to another TKI, and the patient is now clinically stable. <b><i>Discussion/Conclusion:</i></b> Liquid biopsy makes it possible to analyze different genetic alterations that may have implications as predictive factors. It also reveals tumor heterogeneity and its implications for prognostic factors.
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