We report that the cytoplasmic domains of the T-lymphocyte glycoproteins CD4 and CD8α contain short related amino acid sequences that are involved in binding the amino-terminal domain of the intracellular tyrosine protein kinase, p56^lck. Transfer of as few as six amino acid residues from the cytoplasmic domain of the CD8α protein to the cytoplasmic domain of an unrelated protein conferred p56^lck binding to the hybrid protein in HeLa cells. The common sequence motif shared by CD4 and CD8α contains two cysteines, and mutation of either cysteine in the CD4 sequence eliminated binding of p56^lck. p56^lck also contains two cysteine residues within its CD4-CD8α-binding domain, and both are critical to the interaction with CD4 or CD8α. Because the interaction does not involve disulfide bond formation, a metal ion could stabilize the complex.