For many years alkylating agents especially chlorambucil had been considered drugs of choice for first-line treatment of progressive and symptomatic CLL. Subsequently, treatment approaches have included purine nucleoside analogs, fludarabine or cladribine, and monoclonal antibodies (mAb). Moreover, safety and efficacy of bendamustine were investigated in an open-label, randomized, comparative trial. In March 2008 bendamustine was approved by the USA FDA for the treatment of CLL. Recently, several new agents have been explored and have shown promise in treating CLL.These treatments include new mAbs, agents targeting the antiapoptotic bcl-2 family of proteins, receptors involved in mediating survival signals from the microenvironment, antisense oligonucleotides and other agents. The most promising are new mAbs targeted CD20 molecule, lumiliximab, apolizumab, galiximab and anti-CD40 mAbs. Oblimersen, flavopiridol, thalidomide and lenalidomide are also being evaluated both in pre-clinical studies and in early clinical trials.