The mammalian c-fps/fes proto-oncogene encodes a 92-kilodalton cytoplasmic protein-tyrosine kinase (p92c-fes), which is expressed in immature and differentiated hematopoietic cells of the myeloid lineage. To determine the limits of the c-fps/fes locus and to investigate the cis-acting sequences required to direct appropriate tissue-specific expression, a 13-kilobase-pair fragment of human genomic DNA containing the entire c-fps/fes coding sequence was introduced into the mouse germ line. Transcription of the human c-fps/fes transgene was highest in bone marrow and showed a tissue distribution identical to that of the endogenous mouse gene. Macrophages cultured from transgenic mouse bone marrow contained particularly high levels of human and murine c-fps/fes RNA. Furthermore, expression of human c-fps/fes RNA induced a proportionate increase in the level of the p92c-fes protein-tyrosine kinase in bone marrow, bone marrow-derived macrophages, and spleen. Elevated levels of normal human p92c-fes had no obvious effect on mouse development or hematopoiesis. Remarkably, given the short 5'- and 3'-flanking sequences, expression of the human proto-oncogene in bone marrow was independent of integration site, was proportional to the transgene copy number, and was of comparable efficiency to that of the endogenous mouse c-fps/fes gene. The 13-kilobase-pair fragment therefore defines a genetic locus sufficient for the appropriate tissue-specific expression of the fps/fes protein-tyrosine kinase and includes a dominant cis-acting element that directs integration-independent myeloid expression in transgenic mice.