The proto-oncogene Rearranged During Transfection (RET) encodes a receptor tyrosine kinase that is essential for neural, renal, and thyroid development. Pathogenic RET alterations, including mutations and fusions, drive oncogenesis, most notably medullary and papillary thyroid carcinomas and non-small cell lung cancer, by constitutively activating downstream RAS–MAPK, PI3K–AKT, and JAK–STAT signaling. Early multi-kinase inhibitors such as vandetanib and cabozantinib demonstrated modest efficacy with significant toxicity, whereas the selective RET inhibitors selpercatinib and pralsetinib have achieved improved response rates and tolerability. However, resistance remains a key clinical challenge, arising from secondary RET mutations and bypass signaling via MET or EGFR pathways. Continued investigation into next-generation inhibitors and rational combination therapies aims to overcome resistance and optimize treatment sequencing, advancing precision oncology for RET-altered malignancies. Nonetheless, resistance, driven by secondary mutations and bypass signaling, presents a major therapeutic challenge. Ongoing development of next-generation inhibitors and combination strategies aims to overcome resistance and improve patient outcomes.