Serine/threonine-protein kinase BRAF, a downstream effector of the RAS oncogene along the MEK/ERK signaling pathway, has emerged as an important biological marker for diagnosis, prognosis and therapeutic guidance for human cancers. The high prevalence of BRAFV600E activating mutation in papillary thyroid carcinoma, cutaneous malignant melanoma and hairy cell leukemia implies that the mutation is an important ’driver‘ or ’codriver‘ in the development of a subset of these cancers. Diagnostically, the BRAFV600E mutation is a powerful molecular marker for papillary thyroid carcinoma and, quite possibly, hairy cell leukemia as well. Cancers with a BRAF mutation are generally more aggressive than their counterparts without the mutation. Importantly, mutant BRAF has been a highly attractive target for precision cancer therapy. Indeed, recent studies in the clinical trials of BRAF inhibitors in patients with malignant melanoma are changing the treatment paradigm of this highly lethal disease. BRAF mutation testing using highly sensitive and specific methodology in a molecular diagnostic laboratory is essential in the current clinical practice of oncology.