Mycosphaerella graminicola causes Septoria tritici blotch of hexaploid and tetraploid wheat. The inheritance of high-level resistance to Septoria tritici blotch was studied in controlled environment experiments. Intraspecific reciprocal crosses were made between hexaploid wheat lines Salamouni, ST6, Katepwa, and Erik, and the tetraploid wheat lines Coulter and 4B1149. Parental, F1, F2, F3, BC1F1, and BC1F2 populations were evaluated for reaction to isolates MG2 and MG96-36 of M. graminicola. Resistance was controlled by incompletely dominant nuclear genes in all cases. Salamouni had three independent resistance genes to isolate MG2, two of which also controlled resistance to isolate MG96-36. ST6 had a single resistance gene to isolate MG2 and none to isolate MG96-36. The resistance genes in Salamouni and ST6 were not allelic. Two independent genes control resistance to isolate MG2 in Coulter, one of which also controlled resistance to isolate MG96-36. These data are consistent with a gene-for-gene interaction in the wheat-M. graminicola pathosystem.