Abstract Cancer treatment is increasingly guided by molecular analyses designed to identify clinically actionable genomic alterations in individual patients. The discovery of BRAF mutations in human cancer, and the subsequent development and FDA authorization of selective BRAF inhibitors highlight the potential clinical impact and current limitations of precision oncology paradigms. In 2002, Brose and colleagues reported that the distribution of BRAF mutations differed in melanoma and lung cancer and that not all BRAF mutations were functionally equivalent. Here, we discuss this landmark paper, which foreshadowed subsequent research elucidating how biochemical differences among mutant alleles within the same gene and lineage-specific differences among cancer types impact drug sensitivity. Such translational studies provided a road map for the development of novel RAF inhibitors and rational combination strategies that promise greater clinical activity and/or more favorable toxicity profiles. See related article by Brose and colleagues, Cancer Res 2002;62:6997–7000