Constant exposure of plants to harsh environmental conditions generates stress signals perceived by an array of signal transduction cascades that may work together to provide tolerance toward such hostile situations. These signaling pathways often lead to expression of genes involved in biosynthesis or action of several phytohormones. Nitric oxide (NO), a diatomic, gaseous radical, is a major player in plant signaling pathways, which interacts with the signaling routes of salicylic acid (SA), jasmonic acid (JA), and ethylene (ET), and controls the development of plants under stress. NO-mediated posttranslational modifications are often implicated in modulation of plant physiology under altered environments, thus imparting tolerance. This chapter focuses primarily on the present state of knowledge related to NO synthesis, its role as an antioxidant and as a signaling molecule, its interactions with SA, JA, and ET, and the cross-talk between NO and these phytohormones in plants under biotic and abiotic stress. Additionally, an overview of the current status and the challenges of future work are briefly outlined to provide a better understanding of the roles of NO in plant responses.