Butyrate is a naturally occurring 4-carbon fatty acid. Biologically, butyrate has been shown to affect the morphology and growth rate of mammalian cells, as well as induce gene expression. Moreover, butyrate has been proven to serve as an anticancer agent, which unlike others (methotrexate and hydroxyurea), is a nontoxic, safe alternative to cancer treatment. It also induces erythroid differentiation in K562 cells. However, its mechanism of action has yet to be determined. In this study we investigated the effects of sodium butyrate (NaB) on tyrosine phosphorylation in K562 erythroleukemic cells. We demonstrate that NaB induces both dose and time-dependent tyrosine phosphorylation of several proteins, the effects of which were blocked by the tyrosine kinase inhibitor genistein. Furthermore, NaB induces tyrosine phosphorylation and rapid activation of MAP kinase (ERK-1). These findings provide the first evidence that the signal transduction mechanism of NaB involves rapid tyrosine phosphorylation and activation of MAP kinase.