Cross-linking of the antigen receptor on lymphocytes by antigens or antibodies to the receptor results in activation of enzymes of the protein kinase C (PKC) family. Mice homozygous for a targeted disruption of the gene encoding the PKC-beta I and PKC-beta II isoforms develop an immunodeficiency characterized by impaired humoral immune responses and reduced cellular responses of B cells, which is similar to X-linked immunodeficiency in mice. Thus PKC-beta I and PKC-beta II play an important role in B cell activation and may be functionally linked to Bruton’s tyrosine kinase in antigen receptor-mediated signal transduction.