The improved molecular understanding of cancer initiation, progression, and therapeutic resistance has yielded several novel molecular events that are being targeted by emerging therapies. While the treatment of ALL is a success story in the pediatric population, achieving a sustained remission in the adult population remains an area of investigation. Nevertheless, certain therapies have significantly improved the overall survival for adult ALL patients that should continue to improve with the discovery of better molecular targets and targeted agents. Here, we discuss novel therapeutic options under clinical investigation for the treatment of Philadephia chromosome negative ALL including immunotherapy, monoclonal antibodies, and small molecules that may be used as single agent or adjuvant therapy in the management of adult ALL.