The Edmonston (Ed) strain of measles virus (MV) isolated in primary human kidney cells in 1954 has long been thought of as a representative MV strain. But this view has been challenged by wild-type MV strains isolated in marmoset B-lymphoblastoid B95a cells. Although the Ed strain is not pathogenic in monkey models, wild-type MV isolated in B95a cells from measles patients induces clinical signs typical of human measles, indicating that wild-type MV retains its pathogenicity. In addition, wild-type MV has restricted cell tropism and replicates only in B95a and some lymphocyte cell lines. This is in sharp contrast to the ability of the Ed strain to replicate in a variety of human cell lines. To understand the molecular basis for the pathogenicity and the cell tropism of wild-type MV, we have established a reverse genetics system based on a highly pathogenic wild-type MV strain (IC-B) isolated in B95a cells. By using this system, we have constructed recombinant wild-type and Ed strains of MV bearing heterologous envelope hemagglutinin (H) proteins, and we have examined roles of the H protein in determining the cell tropism. Our results clearly indicate that the MV cell tropism is determined by not only the H protein, but also other viral proteins. We thus propose the presence of another unidentified MV receptor on the surface of Vero cells.