Systemic acquired resistance (SAR) is a highly desirable form of resistance that protects against a broad-spectrum of pathogens. SAR involves the generation of a mobile signal at the site of primary infection, which arms distal portions of a plant against subsequent secondary infections. The last decade has witnessed considerable progress and a number of diverse chemical signals contributing to SAR have been isolated and characterized. Among these, salicylic acid (SA) functions in parallel to nitric oxide (NO)- and reactive oxygen species (ROS)-derived signaling leading to SAR. The plant galactolipids monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are also required for SAR and of these DGDG contributes to plant NO as well as SA biosynthesis. Interestingly, both NO deficient or overexpressing plants show compromised SAR, suggesting that NO levels play a critical role in SAR. Epistatic analysis shows that mutations leading to NO deficiency has an compensatory effect on compromised SAR phenotype observed in NO overexpressing plants. SAR in NO overproducer nox1 mutant can also be partially compensated by overexpression of thioredoxin reductase (TRX), which facilitates formation of reduced disulfide bonds. Consequently, a mutation in TRX also compromises SAR. Detailed characterization of NO overproducing plants shows that they are able to make the mobile signal but remain non-responsive to chemical signals that operate in the NO-ROS branch of the SAR pathway. Together, these results suggest an important role of free radicals in systemic signaling.