As new therapeutic approaches have improved responses and outcomes in the treatment of chronic lymphocytic leukemia (CLL), the scientific community focuses now on diagnostic procedures and definitions of response in CLL. The use of monoclonal antibodies in particular has made it possible to treat CLL more effectively. The success of these new therapeutic tools can be traced back to the eradication of detectable disease in a significant number of patients. Therefore, the evaluation of minimal residual disease has become an important end point within clinical trials. This article describes various methods of assessing minimal residual disease and presents data demonstrating that new therapeutic approaches can eliminate residual malignant cells at the highest levels of sensitivity currently available. Although initial evidence suggests that the use of alemtuzumab induces a survival benefit when used in the consolidation setting, important safety issues remain to be resolved before this approach can be introduced in routine practice.