PLX-4032 is a small-molecule, orally available B-Raf kinase inhibitor being developed by Plexxikon Inc and Hoffman-La Roche Ltd for the treatment of cancers harboring activating BRAF mutations. The primary focus of development is in melanoma (> 50% harbor activating BRAF mutations) with other solid tumors, such as colorectal carcinoma (> 10% harbor BRAF mutations), also under investigation. Purified kinase assays have demonstrated that PLX-4032 and its related analogs are highly potent inhibitors of B-Raf activity, with 3-fold selectivity for the V600E mutation over the wild-type kinase. In preclinical models, PLX-4032 and its analogs inhibited the growth of BRAFV600E-positive melanoma cell lines both in vitro and in vivo. In phase I clinical trials, PLX-4032 was well tolerated and objective responses were observed in several patients with BRAFV600E-positive tumors. Responses correlated well with inhibition of intratumoral phospho-ERK and cell proliferation, and reductions in fluorodeoxyglucose uptake on PET scanning. A preliminary analysis of this phase I data suggested that progression-free survival was approximately 7 months, and phase II and III clinical trials are now underway. These studies provide the proof-of-concept for B-Raf as a therapeutic target in melanoma.