Encorafenib (Braftovi™), a BRAF inhibitor, and binimetinib (Mektovi®), a MEK inhibitor, are two orally bioavailable drugs developed by Array BioPharma. In June 2018 they each received their first global approval, in the USA, for use in combination, for patients with unresectable or metastatic melanoma with a BRAFV600E or -V600K mutation as detected by an FDA-approved test. Registration applications for encorafenib and binimetinib for use in combination in the treatment of BRAF-mutation-positive advanced melanoma have also been submitted in the EU, Australia, Switzerland and Japan, with the EMA Committee for Medicinal Products for Human Use adopting a positive opinion in July 2018 towards granting the drugs marketing authorizations in the EU. Encorafenib plus binimetinib combination therapy is also in ongoing phase III clinical development in the treatment of metastatic colorectal cancer. This article summarizes the milestones in the development of encorafenib and binimetinib leading to these first approvals for the treatment of BRAFV600E or -V600K-mutation-positive unresectable or metastatic melanoma.