Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. ActivatingRET alterationscan occur and lead to uncontrolled cellular proliferation as a hallmark of cancer development. OncogenicRETfusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10–20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition,RETmutations are drivers in 60% of sporadic medullary thyroid cancers and 99% of hereditary thyroid cancers. The discovery, rapid clinical translation, and trials leading to FDA approvals of selectiveRETinhibitors, selpercatinib and pralsetinib, have revolutionized the field ofRETprecision therapy. In this article, we review the current status on the use of the selectiveRETinhibitor, selpercatinib, inRETfusion-positive tumors: NSCLC, thyroid cancers, and the more recent tissue-agnostic activity leading to FDA approval.