Ras/Raf/MEK/ERK pathway is a critical downstream signal transduction cascade of most growth factor receptors and is pivotal in oncogenesis, tumor cell malignancy, viral infection, neuronal degeneration, and lymphocyte activation. A number of gain-of-function mutations of Raf genes have been detected in various cancer cells. Moreover, increased MEK/ERK activities were also found in various tumor tissues. Consequently, Raf/MEK/ERK pathway as an anticancer target has been intensively investigated. Numerous small-molecule Raf/MEK/ERK-inhibiting compounds have been reported in the literature and in patent applications. One of Raf inhibitors, the urea derivative Bay 43-9006 (Sorafenib), has recently been approved for treatment of kidney cancer and is under clinical trials for treatment of other cancers. Several Raf inhibitors or mutant B-Raf-selective inhibitors (RAF265 and PLX4032) were also in various stages of clinical trials for cancer treatment. Those inhibitors have also been evaluated preclinically for treatment of viral infection, neuronal degeneration, and inflammatory disease. Thus, small molecule inhibitors of Raf/MEK/ERK pathway may have broad applications in addition to cancer therapy.