The role of BRAF in adult malignancy has been well documented over the last decade and recent data have extended these findings to a number of pediatric cancers. In this and the accompanying articles, we will review the importance of the BRAF pathway in signal transduction resulting in cell proliferation, migration, differentiation, and angiogenesis with a focus on three major pediatric diseases: brain tumors, Langerhans cell histiocytosis (LCH), and melanoma. Mutated BRAF proteins are being identified in an increasing number of pediatric cancers and the development of drugs that can target these mutant proteins offers enormous therapeutic opportunity for these diseases. Because of variations in the types of mutations of BRAF observed in different tumors, particularly those of the central nervous system, an understanding of the feedback loops that regulate monomeric and dimeric BRAF signaling will be critical in selecting the optimal targeted inhibitors. The two most commonly observed alterations in BRAF in patients with brain tumor are the BRAF V600E point mutation and the KIAA1549 truncated fusion and targeting of these will need to differ to account for these feedback loops. Many other factors will influence the activity of novel agents in BRAF activated tumors, including their ability to penetrate the blood-brain barrier (for brain tumors and some patients with LCH) as well as the development of drug resistance and toxicity profiles. Well-controlled trials that take these variables into consideration are already underway and highlight the need for molecular classification of pediatric central nervous system tumors.