Treatment of CLL has been significantly improved through combination of chemotherapy and rituximab. Furthermore, the positive influence of MRD negativity on survival was clearly demonstrated. More recently, drugs with novel modes of action, e.g. targeting B-cell receptor or downstream, chemotherapy-free therapy concepts seem to possible in the near future. More importantly, administration of new drugs with the aim to overcome unfavorable prognostic factors as 17p- or BIRC3, NOTCH1 and SF3B1 is warranted.