Acute lymphoblastic leukemia (ALL) in adults is a very challenging disease. Adults tend to present with higher-risk features and are unable to tolerate chemotherapy regimens as intense as those administered to children. The overall treatment plan for adult ALL is modeled after the pediatric paradigm and includes multi-agent chemotherapy in the forms of induction, consolidation, maintenance, and central nervous system prophylaxis. Most patients will go into complete remission but often relapse; relapse is typically indicative of chemotherapy-refractory disease. Salvage therapy generally consists of cytotoxic agents from drug classes the patient has had limited or no exposure to. The results of conventional chemotherapy for relapsed ALL are unacceptable. The goal of therapy in these patients is to achieve a second remission followed by allogeneic stem-cell transplantation. Monoclonal antibodies directed at cell-surface antigens offer a targeted approach to treating leukemia and other cancers. Anti-CD20 monoclonal antibodies have been shown to improve survival when used in the frontline setting. Novel, highly active antibodies directed at CD19 and CD22 are being investigated in the relapsed and refractory settings. These agents will likely be explored as components of first-line therapy as clinical development continues.