In recent years, considerable advances have been made in first-line treatment strategies for chronic lymphocytic leukemia (CLL). Combination of conventional chemotherapy with immunotherapeutic agents is currently considered the most active strategy, with improved progression-free survival and overall survival. However, patients are not cured and invariably experience relapsing disease requiring treatment. In contrast to the advances made in first-line treatment strategies, much less progress has been made for patients with relapsed and especially refractory CLL. The activity of most chemotherapeutic drugs used in CLL rely on intact p53 function, and repeated cycles of therapy might eventually result in drug resistance because of acquired cytogenetic alterations, mainly affecting genes involved in the p53 response. As a consequence, most commonly used treatment regimens are ineffective in patients with refractory disease. A number of promising alternative treatment approaches are currently under investigation. In this review, the approach to patients with relapsed and refractory CLL and current promising experimental treatment options for these distinct clinical patient categories are discussed.