Reversing or preventing immunodeficiency in patients with chronic lymphocytic leukemia (CLL) is of the highest priority. The past decade of research has met the challenge of treating CLL for most patients. Patients continue to struggle, however, with infections and second primary malignancies related to immunodeficiency. Strategies addressing this need currently are limited to vaccinations, with suboptimal efficacy, and immunoglobulin replacement. Correlative studies have provided insights into immunologic alterations on treatment. Understanding vulnerabilities in the immune system may help identify potential interventions to boost immunity. An emphasis on systematically testing such interventions is required to restore immunocompetence in patients with CLL.