A Drosophila FGF receptor homolog (DFGF-R2/DFRI) termed Heartless (Htl) is expressed in the embryonic mesoderm. The phenotypes of null mutant embryos demonstrated that Htl is a central player that is required for the development of several mesodermal lineages. No abnormalities in the primary specification of the mesoderm were observed. The first defects were seen as irregular migration and spreading of the mesoderm over the ectoderm. Subsequently, cell fates were not induced in several lineages including the visceral mesoderm, heart, and the dorsal somatic muscles. The defects in the induction of cell fates are likely to result from failure of the mesoderm to spread over the ectoderm and receive patterning signals. The defective spreading could be circumvented in htl mutant embryos by providing an ectopic Dpp patterning signal, leading to the formation of heart and dorsal muscle cells. Htl appears to be required also subsequently during the migration and morphogenesis of the different lineages. Expression of a dominant-negative htl construct after the initial induction of cell fates gave rise to aberrant migration and organization of the visceral mesoderm, heart, and somatic muscles. Thus, a common role for Htl in cell migration and tissue organization may account for the pleiotropic defects of the htl mutation.