The mechanisms of speciation have been one of the most debated topics in 
evolutionary biology. Among all reproductive barriers, postzygotic reproductive 
isolation is perhaps the one that has attracted the most attention from 
geneticists. Despite remarkable advances in the identification of loci involved 
in Drosophila speciation, little is known about the genes, functions, and 
biochemical interactions of the molecules underlying hybrid sterility and 
inviability in mammals. Here, we discuss the main evolutionary and molecular 
features that make transcription factors (TFs), especially the family of zinc 
finger proteins with a Krüppel-associated box domain (KRAB-ZNF), strong 
candidates to play an important role in postzygotic reproductive isolation. 
Motivated by the recent identification of the gene encoding PR domain zinc 
finger protein 9 (Prdm9; a KRAB-ZNF gene) as the first hybrid sterility gene 
identified in mammals, we further propose integrative approaches to study 
KRAB-ZNF genes with the main goal of characterizing the molecular pathways and 
interactions involved in hybrid incompatibilities.