<p>Immunotherapy has emerged as one of the mainstays of cancer therapy. To date, immunotherapy research has focused heavily on approaches to modulate the anti-tumor activities of T cells, with other immune components of the tumor microenvironment, including B cells, receiving considerably less attention. Mounting evidence has shown that B cells, plasma cells, and the antibodies they produce can impact tumor control. B cells can have both anti-tumor activity, particularly when organized into tertiary lymphoid structures, and pro-tumorigenic roles in some settings. The rules underlying the complex interplay between B cells, other components of the tumor microenvironment, and the cancer cells themselves are only now being elucidated, but anti-tumor activity appears to be associated with distinct B-cell subpopulations and differentiation trajectories, as well as depending on the class of antibodies produced. Thus, the differentiation state of tumor-infiltrating B cells and the quality of antibodies produced may serve as prognostic markers of favorable patient outcomes. This review focuses on recent research that highlights how B-cell heterogeneity influences anti-cancer immunity and how this knowledge could be harnessed to develop B-cell-based immunotherapies and to fully utilize the power of antibody-based cancer diagnosis and patient stratification.</p>