Simple SummaryThe recent emergence of targeted therapies, including antibody–drug conjugates, bispecific antibodies, and CD19 chimeric antigen receptor (CAR) T cell therapy, revolutionized B-lineage acute lymphoblastic leukemia (B-ALL) management, allowing certain optimism, at least for adult patients with Ph+ B-ALL, on gradually replacing chemotherapy and hematopoietic stem cell transplantation in the first remission. However, to date there are still too few patients that benefit from these new therapies. Therefore, future research directions aim to improve the life expectancy of every patient and especially of those with ALL resistant to available therapeutic strategies. This review provides an overview of new treatment paradigms being used in the relapsed/refractory setting as well as current trials through which these new therapies might be introduced to the frontline setting.AbstractAcute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue. In this review, we will discuss novel therapeutic options including bispecific antibodies, antibody–drug conjugates, chimeric antigen receptor (CAR)-based therapies, and other promising treatments for both pediatric and adult patients.