The recent development of monoclonal antibodies targeting CD19, CD20, and CD22 has significantly improved long-term survival in patients with acute lymphoblastic leukemia (ALL), both in the frontline and relapsed and refractory setting. The incorporation of CD20 monoclonal antibodies (e.g. rituximab) has improved cure rates from 35% to 50% in those with precursor B-cell ALL and from 40 to 80% in those with Burkitt leukemia. More novel antibodies, such as drug conjugates antibodies (e.g. inotuzumab ozogamicin) and bispecific T-cell engagers (e.g. blinatumomab), have shown significant promise in improving outcomes in the relapsed and refractory setting and are currently being studied in the frontline setting, with hopes to further improve long-term outcomes. In this chapter, we will review the role of monoclonal antibodies and how the incorporation of these agents has revolutionized and changed the treatment management of ALL in the frontline setting.