There are several initial therapies available for chronic lymphocytic leukemia (CLL) that offer extended disease-free or treatment-free survival time. However, once patients relapse, particularly after fludarabine-based therapy, treatment choices have remained limited. Newer therapies have now become available, including alemtuzumab, fludarabine-based combinations, rituximab, methylprednisolone, alternative nucleoside analogs, flavopirodol, lenalidomide, signal transduction inhibitors/small molecules, and new monoclonal antibodies. We discuss selection of therapy for the relapsed patient using risk stratification and the role of clinical research in continuing to pursue therapeutic advances against CLL.