The results from experimental studies about genetic factors (‘major genes’) involved in disease resistance and their effects in different genetic backgrounds are reviewed and discussed. The major genes considered are (1) Tv-A and Tv-B, gene loci controlling resistance to infection from avian leukosis virus (ALV), (2) B blood groups which represent the major histocompatibility complex (MHC) of the domestic fowl and are indicators of genetic differences in resistance to Marek's disease (MD) and, only tentatively, (3) endogenous viral (ev) genes which can influence reactions to leukosis infection. For these experiments purebred and crossbred progeny from three genetically different experimental White Leghorn lines have been used extensively. The results concerned with leukosis are based on a comparison between groups of chickens which were homozygous resistant or susceptible to ALV infection. The variability in the amount of damage from leukosis points to interactions between the genotype of resistance to ALV infection and genetic characteristics of the line or lines involved. In this respect the negative influence of ev 6 on the immune response to ALV infection could play a role. To study the association of B blood groups and resistance to MD, an experimental line which still segregated at the B locus (B2, B13, B14 and B21) was crossed with two other lines which were homozygous, respectively, for B2 and B15. Mortality caused by MD in birds carrying the same segregating B blood groups showed a completely different pattern in the two crosses. Rather unexpectedly, the difference in MD mortality was largest between the two types of crossbred layers carrying B21, which points to an interaction between line and B blood group type. Further studies suggested that this interaction depends on genes within the MHC for which the lines crossed might differ. The availability of information from different genetic groups allowed an evaluation of the importance of each ‘major gene’ in relation to the comparative effects of other factors influencing the trait under consideration. Apart from becoming aware of possible interactions resulting from genetic differences between lines, simultaneous results from genetically different experimental lines also provide a safeguard against overestimating or underestimating the potential of such ‘major genes’ for practical utilization in poultry breeding.