Acute lymphoblastic leukemia (ALL) is an aggressive malignancy of lymphoid cells that has historically been difficult to treat, particularly in adult patients, who have poor long-term survival rates with standard intensive chemotherapy. Advances in understanding the underlying biology and molecular mechanisms have resulted in the development of new therapeutic agents. Novel treatment modalities with tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (e.g., rituximab, ofatumumab, inotuzumab), and bispecific T-cell antibodies (e.g., blinatumomab) has changed the landscape of ALL therapy. Addition of these agents to standard, and attenuated, doses of chemotherapy provides significant improvements in survival in the frontline setting. Ongoing studies are evaluating safety and efficacy of chemotherapy-free regimens, especially in older newly diagnosed ALL patients.