Proteins with SH2 or phosphotyrosine binding (PTB) domains bind activated tyrosine kinase receptors and their substrates to propagate signals into cells. Both of the domains recognize phosphotyrosine. Selectivity in these interactions is conferred by short flanking peptide motifs. Therefore, potential exists for modulating tyrosine kinase signaling pathways by the discovery of compounds that selectively bind SH2 and PTB domains. Recent advances with small peptides and nonpeptide compounds suggest that this opportunity can be realized.