Over the past decade, the treatment of patients with chronic lymphocytic leukemia (CLL) has been improved by several new cytostatic agents and monoclonal antibodies. This development has resulted in higher response rates and more profound levels of immunosuppression than with previously used treatments. With the intrinsic immune defect of CLL, the degree and quality of immunosuppression is thus substantially different from that observed during the treatment of other indolent lymphomas and warrants special consideration. Infection with or reactivation of viral diseases such as herpes simplex, varicella zoster, cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B and C or JC virus has become a more frequent problem in the management of these patients. However, most data are derived from observational studies, and only a few interventional trials have been planned and reported. In this review, we summarize the available data, discuss several treatment and management options and offer some recommendations.