Oncogenic mutations in the BRAF gene are detected in ~7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas, papillary thyroid cancer, colorectal cancer, and serous ovarian cancer (1). Over 40 different missense B-RAF mutations have been found and these are clustered in either the glycine-rich P loop or the activation segment of the kinase domain. The vast majority of the mutations (>90%) represent a single nucleotide change resulting in a valine to glutamic acid substitution at residue 600 within the activation segment (^V600EB-RAF). It has been shown that ^V600EB-RAF is able to stimulate endogenous MEK and ERK1/2 phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumourigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA to B-RAF, indicating that B-RAF is an attractive therapeutic target. However, ^V600EB-RAF mutations are detected in benign naevi and premalignant colon polyps which would suggest that this oncogene is not sufficient to induce human tumourigenesis on its own and may require mutations in other genes, particularly tumour suppressor genes (TSGs), to unleash its tumourigenic effects. In a recent publication (2), a more detailed characterisation of the B-RAF mutations detected in human cancer samples was performed. The mutants were grouped into three different classes depending on their level of activity in COS cell transfections. High activity mutants were classed as those having more basal kinase activity than ^WTB-Raf stimulated by ^G12VRAS with ^V600EB-RAF being an example of this class. Intermediate activity mutants were classed as those having more basal kinase activity than ^WTB-Raf but less than ^WTB-Raf stimulated by ^G12VRAS. Impaired activity mutants were classed as those having ~30-80% less basal kinase activity than ^WTB-Raf. The high and intermediate activity mutants all stimulated endogenous MEK and ERK1/2 phosphorylation and all impaired activity mutants except one also stimulated ERK phosphorylation via activation of endogenous C-RAF. The one remaining impaired activity mutant, ^D594VB-RAF, did not stimulate ERK phosphorylation or C-RAF activity suggesting that its role in human oncogenesis is complex. Many questions need to be addressed in understanding the role of oncogenic B-RAF in human cancer development. For example, we need to gain complete insight into the role of oncogenic B-RAF in cancer development in vivo, whether it collaborates with TSGs or other oncogenes, and what downstream signalling pathways are activated by this oncogene. It is also important to understand how each of the three classes of B-RAF mutants contribute to tumourigenesis and the role of C-RAF in mediating their effects. In order to address these various questions, we have used gene targeting in mice to generate conditional knockin alleles, using Cre-lox technology, that are characteristic of each class of B-RAF mutant found in human cancer (3). In these alleles, expression of oncogenic B-raf is dependent on the presence of the Cre recombinase; in its absence wild-type B-raf is expressed. Our research is aimed at using specific Cre activation methods to induce oncogenic B-raf expression in various adult somatic tissues, with particular emphasis on melanocytes and colonocytes. Progress on our work with these mouse models will be discussed.