The recent US Food and Drug Administration (FDA) approval of the dabrafenib/trametinib combination as a tissue-agnostic treatment for solid tumors with BRAF V600E mutation is the result of more than 20 years of extensive research into BRAF mutations in human cancer, the underlying biological mechanisms that drive BRAF-mediated tumor growth, and the clinical testing and refinement of selective RAF and MEK kinase inhibitors. Such approval marks a significant achievement in the field of oncology and represents a major step forward in our ability to treat cancer. Early evidence supported the use of dabrafenib/trametinib combination in melanoma, non–small-cell lung cancer, and anaplastic thyroid cancer. Furthermore, data from basket trials have demonstrated consistently good response rates in various tumors, including biliary tract cancer, low-grade glioma, high-grade glioma, hairy cell leukemia, and multiple other malignancies, which has been the basis for FDA approval of a tissue-agnostic indication in adult and pediatric patients with BRAF V600E–positive solid tumors. From a clinical standpoint, our review delves into the efficacy of the dabrafenib/trametinib combination for BRAF V600E–positive tumors: examining the underlying rationale for its use, evaluating the latest evidence on its potential benefits, and discussing the possible associated adverse effects and strategies to minimize their impact. Additionally, we explore potential resistance mechanisms and future landscape of BRAF-targeted therapies.