Although modern treatment options for B-chronic lymphocytic leukemia (CLL) produce high response rates, virtually all patients relapse, presumably due to the persistence of minimal residual disease (MRD). Novel approaches that maintain response and therefore delay growth of MRD may ultimately improve survival outcomes. In CLL, any type of continued therapy must be not only well tolerated but also convenient to ensure compliance. There has been some exploration of rituximab as maintenance therapy in CLL; however, given its limited clinical activity as a single agent, other options need to be studied. One such agent is the immunomodulatory drug lenalidomide, which has demonstrated clinical activity both in patients with relapsed or refractory CLL and in the frontline setting. Other attractive agents being explored in the maintenance setting include epigallocatechin gallate, curcumin, and the citrus pectin-derived galectin-3 inhibitor GCS-100. These naturally occurring compounds are well tolerated, and they inhibit survival signals in the microenvironment necessary for tumor development, making them well suited for evaluation as maintenance therapy for CLL.