The management of chronic lymphocytic leukemia (CLL) is currently undergoing a profound change. First, several new drugs have been approved (fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab). In addition, novel monoclonal antibodies targeting CD20, CD23, CD37 or CD40, as well as drugs designed to interfere with central pathways regulating the cell cycle, the apoptotic machinery, or the leukemic microenvironment (flavopiridol, oblimersen, ABT-263 or lenalidomide) are being tested in clinical trials. Furthermore, improved protocols using reduced-intensity allogeneic progenitor cell transplantation makes it possible to offer this procedure to more patients with CLL. Finally, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current knowledge in this rapidly moving field.