Over the past decade, researchers have tried to tackle RET-driven cancers with various multikinase inhibitors. However, their efficacy was only modest and came at the cost of significant toxicities, leading to high rates of treatment discontinuation. Therefore, the development of RET-specific inhibitors has become paramount. Recently, the highly selective RET tyrosine kinase inhibitors selpercatinib and pralsetinib have demonstrated high response rates in patients with RET-altered non-small cell lung cancer (NSCLC) and thyroid cancer. As brain metastases eventually occur in approximately 50% of patients with RET fusion-positive NSCLC, special attention should go to the intracranial activity of these drugs.