Advances in chemotherapy administration have made acute lymphoblastic leukemia (ALL) a curable disease; however, most patients will relapse, despite readily attaining a complete remission. Treatment of relapse has shown dismal results with little advances made in the recent decades. Antigenic-directed therapy of ALL can complement cytotoxic chemotherapy and has shown encouraging results. This review will evaluate four antigens in ALL (CD20, CD22, CD52, and CD19) and therapeutic strategies to target them. We will review the clinical and preclinical data surrounding rituximab, epratuzumab, inotuzumab ozogamicin, alemtuzumab, blinatumomab, and chimeric antigen receptor-modified T-cell therapy.