The last decade has seen major progress in our understanding of the pathobiology of chronic lymphocytic leukemia (CLL) and the identification of potential new therapeutic targets. As a result, researchers have developed novel targeted therapies, several of which are already approved and many of which are in advanced stages of clinical development. These new agents are much less toxic than chemoimmunotherapy and may be preferred for their superior efficacy in patients with certain high-risk features, such as del(17p). The place of these therapies in CLL management is becoming better defined, and they are gradually replacing traditional forms of chemoimmunotherapy. This review provides an update on the clinical data regarding various signal transduction inhibitors in CLL.