Chemoimmunotherapy is the new gold standard of therapy for patients with advanced chronic lymphocytic leukemia (CLL). However, in spite of the high complete response rate achieved with chemoimmunotherapy, all patients eventually relapse and CLL is still incurable. Newer and more rationally developed compounds are clearly needed for these patients, in particular those with refractory disease. Among these agents, novel monoclonal antibodies, cyclin-dependent kinase inhibitors, chromokine receptor antagonists, lenalidomide, signal transduction inhibitors and pro-apoptotic molecules have recently shown some efficacy in patients with relapsed or refractory disease. Hopefully, the combined use of these agents in risk-adapted treatment strategies will improve the outcome of patients with CLL and set the stage for their cure.