It has recently been postulated that immunoglobulin class switching is preceded by transcription from unrearranged heavy chain genes. In this report, we have investigated the conditons under which RNA transcribed from unrearranged Cγ3, Cγ1, Cγ2b, Cγ2a, Cϵ and Cα genes are induced in normal spleen cells by mitogens and/or interleukin (IL)4, IL5 and interferon-γ. Lipopolysaccharide (LPS) plus IL4 induced germ-line γ1 and ϵ transcripts. LPS induced γ2b and γ3 transcripts and high doses of IL4 suppressed these LPS-induced transcripts. Interferon-γ induced low levels of germ-line γ2a transcripts and profoundly suppressed the γ1 and ϵ transcripts induced by LPS and IL4. IL5 alone or in combination with IL4 and/or LPS did not induce germ-line α transcripts. Spleen cells of the partially immunodeficient mice CBA/N and C3H/HeJ, which do not express IgG3 could be induced, however, by polyclonal activators to express germ-line γ3 and γ2b transcripts. The data indicate that the capacity of a ligand to induce/suppress transcription of a particular unrearranged heavychain gene is a good indicator of its capacity to induce switching to the corresponding Ig isotype. However, it is also clear that control of switching can be carried out at other levels.