Evolution of frontline treatment for patients with chronic lymphocytic leukemia (CLL) has been driven by the objective of increasing complete remission (CR) rates and achieving maximum elimination of leukemia. As a result, effective combination regimens incorporating new agents such as monoclonal antibodies have been developed. Beyond morphologic CR, evaluation for residual disease by multicolor flow cytometry or molecular techniques may provide a tool to assess potentially more effective therapies. Although new prognostic factors correlate with time to treatment and survival have been identified, the utility of these factors in predicting response rates or response duration has not been established. Clearly, strides have been made in developing effective treatments that are improving remission duration with the ultimate goal of improving survival for patients with CLL. Herein, we review the recent progress in frontline therapies for patients with CLL.