While it is well established that T cells play a prominent role in regulating Ig isotype switching in response to T-cell-dependent (TD) antigens, the events which control this process in response to antigens that do not recruit antigen-specific T cells (T-cell-independent (TI) antigens) is less clear. In this article, Clifford Snapper and James Mond suggest that the nature of the B-cell activator, in combination with cytokines produced by antigen non-specific cells, including macrophages, NK cells, and polyclonally activated B cells, may play an important role in the process leading to Ig isotype switching in response to TI antigens.