The RAF-MEK and PI3K-AKT pathways are both frequently deregulated in cancer, and often play a critical role in oncogenesis. In the previous years, major progress has been made in the development of targeted drugs against signaling kinases which are involved in carcinogenesis. Currently, targeted drugs against RAF, MEK, PI3K and AKT (among several others) have entered clinical investigation. Here we describe tumor causing mutations of these kinases, as well as the small molecule inhibitors that target these kinases, which contributes to improved ways of treating human cancer.