Over the past several decades the important progress has been made in the management of acute lymphoblastic leukemia (ALL), especially among children. However, in adult patients reported cure rates seldom exceeded 40%, despite the use of hematopoietic stem-cell transplantation in many cases. Conventional chemotherapy is toxic and ineffective. Therefore, new treatment options and risk-adapted therapies are needed to improve the outcome of ALL patients. This review is focused on new systemic treatment modalities, such as nucleoside analogues, purine synthetase inhibitors, monoclonal antibodies, tyrosine kinase inhibitors and other agents targeting molecular pathways that are aimed to benefit patients and improve the outcome of their treatment.