Although fludarabine-based regimens and monoclonal antibodies are able to induce high overall and complete remission rates in patients with chronic lymphocytic leukemia (CLL), a major impact on overall survival or even potential cure by these treatments is still lacking. Increased sensitivity and specificity of flow cytometry and polymerase chain reaction techniques enable us to detect few CLL cells in peripheral blood and bone morrow. This has brought significant advancement into the evaluation of response quality of CLL treatment. The eradication of minimal residual disease (MRD) below measurable levels seems to be critical to overcome recurring clonal expansion resulting in disease progression or relapse. Several studies suggest that achieving MRD negativity in patients with CLL provokes prolonged response duration and survival. Thus, elimination of MRD should become a surrogate end point of modern clinical trials and a goal in CLL. This review summarizes the current status of and future strategies for MRD eradication in CLL.