A hypothetical scenario of mixed populations of Busseola fusca (Fuller) (Lepidoptera: Noctuidae), Chilo partellus (Swinhoe) (Lepidoptera: Crambidae), and Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) was used as a model to investigate the potential effects of mixed populations of lepidopteran pests, on the design and implementation of insect resistance management (IRM) strategies for Bt maize (L.) (Poaceae) on smallholder farms in Africa. To predict the structure of such mixed populations in different agroecological zones, the biological and behavioral characteristics that affect the competitiveness of these species were identified and analyzed. Additionally, the validity of the assumptions that underlie the high-dose/refuge strategy was compared among the three species. Differences between the species, and the influence thereof on the choice of IRM strategy for a specific environment, were explored through analysis of three hypothetical scenarios. We suggest that the use of separate refuges as a component of an IRM strategy against mixed pest populations in smallholder Bt maize fields may be unwise. A seed mixture approach, coupled with an effective integrated pest management (IPM) strategy, would be more practical and sensible since it could limit the opportunity for a single species to dominate the species complex. The dynamic interactions in a multi-species community and domination of the species complex by a single species may influence moth and larval response to maize plants, which could lead to an increased infestation of Bt plants, and subsequent increased selection pressure for resistance evolution. This article provides insights into the unique challenges that face the deployment of Bt maize in Africa.