Tropomodulin (Tmod) is a tropomyosin (TM)-binding protein that caps the pointed end of the actin filaments and regulates the length of actin filaments in muscle and non-muscle cells. Mouse embryonic stem (ES) cells which normally express tropomodulin survived the targeted disruption of one and two Tmod alleles. Interbreeding of Tmod +/- mice derived from Tmod +/- ES cells, however, has not generated Tmod -/- littermates, suggesting a possible lethality of the homozygous Tmod-null mutation during embryogenesis. While Tmod +/- mice appeared to have normal RBC counts, significant reduction (36%) in the platelet number and increase (32%) in platelet volume were found. The expression of tropomodulin in normal ES cells, the lack of Tmod -/- littermates, and changes found in platelets of Tmod -/- mice suggest important functional roles of tropomodulin in adult cells and tissues and the embryogenesis of mice.