T cells with helper activity can be found in mice that lack expression of the CD4 glycoprotein. The CD4 promoter is active in these cells; they respond to antigens presented by MHC class II molecules; they do not express CD8 and they do not depend on MHC class I for their development. By such criteria, these CD8 T cells resemble normal CD4+helper T cells. The development of the helper lineage in CD4-null mice can be potentiated by expression of transgenes that encode either wild type CD4, or a deletion mutant of CD4 that lacks the cytoplasmic tail and therefore cannot interact with the tyrosine kinase p56Ick. These observations suggest that CD4 is not absolutely required for the specification of the helper cell lineage. The role of the CD4 molecule in the development of T cells and possible mechanisms by which it achieves its functions are discussed.