Chronic lymphoid leukemias include well defined mature B-cell and T-cell neoplasms with diverse natural history and specific morphological, immunophenotypic and molecular characteristics. The most common adult leukemia in the Western world is chronic lymphocytic leukemia (CLL). Rarer indolent lymphoid leukemias include prolymphocytic leukemia, hairy cell leukemia, large granular lymphocyte leukemia and T-cell leukemia/lymphoma. Recently, several new agents have been explored and have shown promise in CLL treatment. Novel therapies are being evaluated both in pre-clinical studies and in early clinical trials. These treatments include new purine nucleoside analogs, antisense oligonucleotides, agents targeting the antiapoptotic Bcl-2 family of proteins, receptors involved in mediation of survival signals from the microenvironment, cyclin-dependent kinase inhibitors, protein kinase C inhibitors, tyrosine kinase inhibitors, immunomodulating drugs, new monoclonal antibodies and other agents. At present, available therapies are only partially efficient and there is an obvious need to develop better strategies and new, more specific and active drugs. This review will focus on agents currently being explored in preclinical studies and in early clinical trials.