Infections remain a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of these complications is related to immune defects inherent to the primary disease as well as to therapy-related immunosuppression. The spectrum of infections seen has evolved with the therapeutic use of purine analogs, which induce specific cellular immune defects, as well as the monoclonal antibodies alemtuzumab and rituximab. Although bacterial infections are most common, fungal and herpesvirus infections are also seen with use of these agents. This overview will summarize the pathogenesis of infection in patients with CLL as well as the spectrum of infection and approaches to the prophylactic and therapeutic management of these complications.