Second malignancies are frequent complications in patients with chronic lymphocytic leukemia (CLL). Patients with this leukemia may develop large cell lymphoma (LCL) known as Richter's syndrome (RS). RS occurs in CLL patients of about 3% and may develop in a single lymph node or more often in a group of nodes. However, in some patients extranodal localization of aggressive lymphoma in RS has been observed. Besides LCL, Hodgkin's disease, prolymphocytoid leukemia, multiple myeloma and acute lymphoblastic leukemia may also occur as RS variants. The origin of lymphoid cells in RS remains tentative. However, CLL and RS originate from the same clone for some patients, whereas, in other patients cells of aggressive lymphoma do not have the features of the same clone as the CLL cells. The prognosis of RS is poor. Survival in different studies will be usually 2-5 months. The secondary development or coexistence of myeloproliferative disorders or myelodysplastic syndrome and solid tumors have also been rarely documented in CLL patients. It is of great concern that therapy may further increase the risk of a second neoplasm. However, until now, there are no clear evidence that alkylating agents or purine nucleoside analogs may be associated with an increased incidence of second malignancies in patients with CLL. In this review, epidemiology, biology, clinical characteristic and treatment approaches in RS and other secondary neoplasms in patients with CLL are discussed.