Despite progress in the treatment of B cell disorders, novel treatment approaches are still highly needed. CD19 is a pan-B cell marker that is recognized as a potential immunotherapy target for B cell disorders, including blood-borne malignancies and autoimmune diseases. Although initial attempts to target CD19 were unsuccessful, a new wave of investigational agents is currently in development. These agents are based on novel antibody-based technologies and formats that appear to better exploit CD19's therapeutic potential, and some promising clinical study data has already been reported. This review provides an overview and the rationale for the most advanced CD19-targeting programs in development.