Biotic and abiotic stresses impose a serious limitation on crop productivity worldwide. Prior or simultaneous exposure to one type of stress often affects the plant response to other stresses, indicating extensive overlap and crosstalk between stress-response signaling pathways. Systems biology approaches that integrate large genomic and proteomic data sets have facilitated identification of candidate genes that govern this stress-regulatory crosstalk. Recently, we constructed a yeast two-hybrid map around three rice proteins that control the response to biotic and abiotic stresses, namely the immune receptor XA21, which confers resistance to the Gram-negative bacterium, Xanthomonas oryzae pv. oryzae; NH1, the rice ortholog of NPR1, a key regulator of systemic acquired resistance; and the ethylene-responsive transcription factor, SUB1A, which confers tolerance to submergence stress. These studies coupled with transcriptional profiling and co-expression analyses identified a suite of proteins that are positioned at the interface of biotic and abiotic stress responses, including mitogen-activated protein kinase 5 (OsMPK5), wall-associated kinase 25 (WAK25), sucrose non-fermenting-1-related protein kinase-1 (SnRK1), SUB1A binding protein 23 (SAB23), and several WRKY family transcription factors. Emerging evidence suggests that these genes orchestrate crosstalk between biotic and abiotic stresses through a variety of mechanisms, including regulation of cellular energy homeostasis and modification of synergistic and/or antagonistic interactions between the stress hormones salicylic acid, ethylene, jasmonic acid, and abscisic acid.