The plant stress hormone abscisic acid (ABA) regulates myriad of plant developmental programs such as germination, root development, vegetative growth, seed development, dormancy, and seed desiccation tolerance. ABA, the master controller of transpiration, regulates ion channels and gene expression that are necessary for abiotic stress tolerance of plants and hence popularly called as the plant stress hormone. In the past one decade, the role of ABA in regulation of biotic stress tolerance is emerging. In response to low leaf water status as well as pathogen-associated molecular pattern (PAMP) signaling, ABA induces closure of stomata, which are major gateways of pathogens entry into plant cells. Salicylic acid (SA) promotes systemic acquired resistance (SAR) to biotrophic lifestyle, while jasmonic acid (JA) and ethylene positively regulate induced systemic resistance (ISR) against necrotrophic pathogens and insects. In addition to its role in PAMP-mediated stomatal closure, ABA interacts synergistically or antagonistically with SA, JA, and ethylene to regulate disease resistance pathway. Intense efforts made since 1980s have unraveled the molecular details of ABA signaling, culminating with the breakthrough discovery of the START domain proteins PYR/PYL/RCAR as ABA receptors (ABAR) and identifi cation of core components of ABA signaling in 2009. Recent studies have also revealed the critical role of ABA receptors in plant processes such as fruit ripening and secondary metabolite accumulation. Genetic manipulation of ABA signaling is envisaged as a potential tool for enhancing plant development and biotic and abiotic stress tolerance of crops. This chapter focuses on molecular and structural basis of ABA signaling. Further, it explores the potential of genetic engineering of core components, protein engineering to develop orthogonal receptor, and development of novel synthetic agonists of ABARs for improving crop yield, quality, and stress tolerance.