The Dobzhansky–Muller (D–M) model of reproductive isolation (RI) posits that hybrid sterility and inviability result from negative epistatic interactions between alleles at a minimum of two genes. This standard model makes several implicit assumptions, including a lack of environmental effects and genotype-by-environment interactions (GEI) involving hybrid sterility and hybrid inviability loci. Here we relax this assumption of the standard D–M model. By doing so, several patterns of the genetic architecture of RI change. First, a novel single-locus model of postzygotic RI emerges. Several indirect lines of evidence are discussed in support of the model, but we conclude that this new single-locus model is currently no more supported than previous ones. Second, when multilocus D–M models incorporating GEI are considered, we find that the number of potential negative epistatic interactions increases dramatically over the number predicted by the standard D–M model, even when only the most simple case of two-allele interactions are considered. Third, these multilocus models suggest that some previous generalizations about the evolutionary genetics of postzygotic RI may not necessarily hold. Our findings also suggest that the evolution of postzygotic RI may be more likely when the expression of traits driving speciation is affected by the environment, since there appears to be a greater spectrum of potential hybrid incompatibilities under the D–M model incorporating GEI.