Activating somatic mutations in the BRAF protooncogene were recently discovered in a wide variety of malignancies, and most notably so in melanoma (? 60%–70% of cases)(Brose et al., 2002; Davies et al., 2002; Satyamoorthy et al., 2003), papillary thyroid cancer (? 35%–70%)(Cohen et al., 2003; Kimura et al., 2003), and colon cancer (? 10%)(Davies et al., 2002; Rajagopalan et al., 2002; Yuen et al., 2002). Tumor-derived BRAF alleles encode oncoproteins with constitutive serine/threonine kinase activity, and when ectopically expressed in immortalized cell lines, they cause hyperstimulation of the MAP kinase cascade and cellular transformation (Davies et al., 2002). Preliminary studies suggest that B-Raf is a promising target for drug development in melanoma and other malignancies that depend upon B-Raf signaling. The potential importance of mutant BRAF alleles in tumorigenesis becomes apparent upon examining the function of Raf kinases in normal cellular physiology (see Table 1 and Figure 1). BRAF is a member of the Raf family of protein kinases, which includes CRAF, BRAF, and ARAF (Chong et al., 2003; Mercer and Pritchard, 2003). Expression of all three RAF genes can be detected in most tissues, with prominent expression of BRAF in neuronal tissue and ARAF in urogenital tissue. The entire RAF gene family is necessary for normal murine development, with the expression of both CRAF and BRAF required to complete gestation (Chong et al., 2003; Mercer and Pritchard, 2003). A diverse number of stimuli such as mitogens, hormones, and neurotransmitters promote the activation of Raf kinases by first triggering increases in the levels of Ras-GTP in cells. The GTP-bound forms of Ras directly bind and thereby recruit cytosolic dimers of Raf kinases to the plasma membrane, where Raf is activated through phosphorylation by other kinases and potentially by autophosphorylation (Chong et al., 2003; Mercer and Pritchard, 2003). Activated and membraneassociated Raf assembles a MAP kinase signaling complex that consists of two classes of kinases, MEK and ERK, and scaffolding proteins, including KSR, CNK, and RKIP (Chong et al., 2003). The MAP kinase cascade initiates with the phosphorylation and activation of MEK by Raf, and the subsequent phosphorylation and activation of ERK by MEK. Active ERK