Transcriptional control plays an important role in regulating submergence responses in plants. Although numerous genes are highly induced during hypoxia, their individual roles in hypoxic responses are still poorly understood. Through microarray studies, we identified a number of transcription factors (TF) that are induced in different stages of hypoxia. We have chosen two TFs, AtHRE1, which was specifically induced during hypoxia but not by cold, drought or dehydration, and WRKY22, which was rapidly and strongly induced upon submergence in Arabidopsis, for further studies. Our results suggest that in addition to ethylene an ethylene-independent signal is also required to mediate hypoxia induction of HRE1. Through a series of genetic and molecular analyses, we found that hypoxia-inducible genes could be affected by AtHRE1-RNAi lines in two different ways: hypoxic induction of glycolytic and fermentative genes was reduced, whereas induction of a number of peroxidase and cytochrome P450 genes was increased. Taken together, our results show that AtERF73/HRE1 is involved in modulating ethylene responses under both normoxia and hypoxia. We found that many genes in the WRKY transcription factor (TF) family were rapidly and strongly induced upon submergence in Arabidopsis. Notably, a large proportion of innate immunity marker genes were co-induced with WRKYs under submergence and other stresses. Compared to wild-type, WRKY22 T-DNA insertion mutants, wrky22-ko1 and wrky22-ko2, have lower submergence-acclimatized disease resistance. Submergence induction of innate immunity markers, such as FRK1 and WRKY53, were lower in these WRKY22 mutants. These results provide evidence that submergence triggers Arabidopsis immunity through WRKY22, allowing plants to defend simultaneous or sequential infection upon floods.