Infections continue to be a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), as therapeutic advances have occurred over the past several decades. The pathogenesis of infection in these patients is multifactorial, including inherent immune defects related to the primary disease process, such as hypogammaglobulinemia, as well as therapy-related immunosuppression. A characteristic spectrum of infectious complications has been described for specific treatment agents. With chlorambucil, most infections are bacterial in origin, caused by common Gram-positive and -negative organisms. Recurrent infections are a hallmark, with the respiratory tract being the most common site of infection. The pathogenesis of infection with the purine analogues is related to the quantitative and qualitative T-cell abnormalities induced by these agents. Risk factors for infection identified in patients treated with fludarabine include advanced-stage disease, prior CLL therapy, response to therapy, elevated serum creatinine, hemoglobin < 12 g/dL, and decreased serum IgG. As compared with patients receiving chlorambucil, patients receiving fludarabine have more major infections and herpes virus infections. However, Pneumocystis, Aspergillus, and cytomegalovirus (CMV) infections are uncommon. The use of alemtuzumab is complicated by frequent opportunistic infections. CMV reactivation is especially problematic, occurring in 10%-25% of patients. For prevention of infection, the use of vaccinations and immunoglobulin replacement has been studied. Recommendations for prophylactic antimicrobial therapy have arisen from CLL treatment trials and anecdotal reports. As new treatment approaches are developed for CLL, one must consider not only the efficacy of these agents for disease response but also the effect on subsequent infectious complications. Infectious complications remain a significant cause of morbidity and mortality in patients with CLL. We will review the pathogenesis as well as the spectrum of infections in these patients. We will also discuss approaches to the prophylactic and therapeutic management of infections in these patients.